Hypoxic-Ischemic Injury in the Term Infant

Chapter Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy Terrie E. Inder

◆

Joseph J. Volpe

The clinical aspects of neonatal hypoxic-ischemic encephalopathy (HIE) are appropriately discussed following the neuropathology (see Chapter 18) and pathophysiology (see Chapter 19), because understanding of the clinical phenomena is facilitated greatly by an awareness of the underlying pathological substrates. Moreover, choice of appropriate diagnostic modalities, formulation of rational prognostic statements, and development of appropriate plans of management are based, in many ways, on awareness of the probable neuropathologies. In this chapter, we discuss the clinical settings for neonatal HIE, the clinical syndrome, diagnostic studies, clinical correlations, prognosis, and management.

CLINICAL SETTINGS The importance of the early recognition of the clinical risk factors for hypoxic-ischemic cerebral injury in the term born infant has escalated significantly in the last decade with the implementation of successful neuroprotection with therapeutic hypothermia (see later sections). To initiate such therapy requires a recognition of the infant who may have suffered hypoxic-ischemic cerebral injury—predominantly in the peripartum period. The peripartum period is defined as the period shortly before, during, and immediately after birth. The clinical settings for neonatal HIE are dominated by the ultimate occurrence of ischemia (i.e., diminished blood supply to brain), usually, but not necessarily, preceded or accompanied by hypoxemia (i.e., a diminished amount of oxygen in the blood supply). Hypoxemia leads to brain injury principally by causing myocardial disturbance and loss of cerebrovascular autoregulation, with ischemia the major consequence. The temporal characteristics and the severity of the hypoxemia and ischemia, as well as the gestational age of the infant, are the principal determinants of the type of resulting neuropathology (see Chapters 18 and 19). The major causes of serious hypoxemia in the peripartum period are: (1) hypoxia-ischemia with intrauterine disturbance of gas exchange across the placenta (i.e., asphyxia) or with failure to establish independent respiration at the time of birth or both; (2) postnatal respiratory insufficiency secondary to severe respiratory disease; and (3) severe right-to-left shunt secondary to persistent fetal circulation or cardiac disease. The major causes of serious ischemia are: (1) intrauterine asphyxia (i.e., hypoxemia, hypercarbia, and acidosis) with cardiac insufficiency and loss of cerebrovascular autoregulation both in 510

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utero and at the time of birth; (2) postnatal cardiac insufficiency secondary to severe hypoxemia or congenital heart disease; and (3) postnatal (postcardiac) circulatory insufficiency secondary to patent ductus arteriosus (with “ductal steal”) or vascular collapse (e.g., with sepsis). In this chapter, we will focus on the encephalopathic syndrome in the term infant and the presence of evidence for peripartum hypoxic-ischemic injury. We prefer the term “peripartum” hypoxic-ischemic injury as it acknowledges the potential presence of (1) fetal or maternal prepartum conditions that may accentuate propensity to intrapartum hypoxic-ischemic injury; (2) intrapartum hypoxic–ischemic injury per se; and (3) the often associated protracted postpartum resuscitative efforts for such infants, with no or low heart rate for several minutes. Although the postnatal cardiac compromise is not the primary etiology of the poor birth transition, it may contribute to the extent of the ultimate hypoxic-ischemic cerebral injury in the infant. However, there is also evidence that even with prolonged resuscitation, in the era of therapeutic hypothermia there can be better outcomes than might be expected (see the section on prognosis).1 It is important to recognize that not all neonatal encephalopathies are related to hypoxic-ischemic disease. Antepartum and postpartum disorders (e.g., infectious, metabolic, dysgenetic) may lead to neonatal encephalopathies, 2,3 as discussed throughout this book. In one large population-based observational study, the prevalence of moderate to severe encephalopathy was 1.64 per 1000 live term births, and the prevalence of “birth asphyxia” was 0.86 per 1000 live term births.4 Fully 56% of all cases of newborn encephalopathy were related to hypoxic-ischemic injury that occurred during the intrapartum period. These findings are consistent with a more recent large cohort study of 4165 singleton term infants with any one of the following: seizures, stupor, coma, Apgar score at 5 minutes less than 3 and/or receiving hypothermia therapy.5 In this study, 15% of the infants experienced a clinically recognized sentinel event, such as antenatal hemorrhage (presumably, often placental abruption), uterine rupture, or cord prolapse, all of which are capable of compromising oxygen supply. Almost one half of the infants displayed umbilical cord blood gas acidemia and/or fetal bradycardia. Of note, signs of inflammation were also not uncommon with 27% of mothers displaying elevated maternal temperature in labor and 11% clinical chorioamnionitis. However, the contributing role of chorioamnionitis is not consistently supported.6 Although intrapartum sentinel events provide clear

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy evidence of a hypoxic-ischemic insult, in three studies of neonatal encephalopathy, sentinel intrapartum events were only identified in 8% to 25% of infants.7-9 In a referral sample of 500 term infants with neonatal encephalopathy evaluated for therapeutic hypothermia, 48 (9%) had a sentinel birth event.10 Thus, it can be challenging to confirm an hypoxic-ischemic etiology for the infant with neonatal encephalopathy and/or the need for resuscitation as only 10% to 20% of such infants may have a clinical history of a major risk factor, whereas approximately 50% or more may have a constellation of risk factors including maternal history, cord acidemia, and the need for resuscitation that supports this as the most likely etiology for their neurological syndrome. In addition, although obvious, hypoxic-ischemic injury may affect the infant’s brain during the antepartum and postnatal periods, albeit much less commonly than the intrapartum period. On the basis of earlier work,11-27 approximately 20% of hypoxic-ischemic injury recognized in the newborn period was said to be related primarily to antepartum insults. These data should be interpreted with the awareness that assessment of timing of insults to the fetus in these reports generally was based on imprecise methods, and the variability of findings is considerable. Moreover, more recent studies with consistent use of magnetic resonance imaging (MRI) suggest that the large majority of hypoxic-ischemic injury occurs during the intrapartum period. The best data indicate that most infants with neonatal HIE and intrapartum evidence of hypoxic-ischemic insult exhibit, on MRI, evidence only of injury from the immediate peripartum period with no clear evidence of long-standing antenatal hypoxic-ischemic disease (Table 20.1).28,29 In one study of 245 term infants with neonatal encephalopathy and evidence of intrauterine asphyxia, fully 80% had evidence of acute lesions (within the period immediately before or during labor and delivery) consistent with hypoxic-ischemic disease, 16% had normal MRI scans, and only 4% had concomitant evidence of chronic antenatal injury (see Table 20.1).28 In another MRI study of 173 term newborns with encephalopathy and signs of intrauterine asphyxia, only acute injury was observed.29 Related clinical and epidemiological data also support a marked preponderance of intrapartum events in the origin of neonatal HIE, especially in the term infant.30-32 The principal intrapartum events leading to hypoxic-ischemic fetal insults include acute placental or umbilical cord disturbances, such as abruptio placentae or cord prolapse, prolonged labor with transverse arrest, difficult forceps

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extractions, or rotational maneuvers (see Chapters 17 to 19). Postpartum events alone (e.g., severe persistent fetal circulation, severe recurrent apneic spells, cardiac failure secondary to large patent ductus arteriosus or other congenital heart disease, severe pulmonary disease) may lead to HIE and may account for approximately 5% to 10% of cases. 30 Most of these and related postnatal factors are much more important in the pathogenesis of hypoxic-ischemic brain injury in the premature infant than in the term infant (see Chapters 14 to 16). Although hypoxic-ischemic injury certainly can occur in the antepartum period (e.g., secondary to maternal trauma, maternal hypotension, uterine hemorrhage), this injury cumulatively accounts for between 5% and 20% of neonatal HIE (as noted earlier). However, antepartum factors appear to be of some importance in the risk for neonatal encephalopathy related to peripartum events. Such factors may indeed predispose to intrapartum hypoxia-ischemia during the stresses of labor and delivery, especially through threats to placental flow. Such factors include maternal diabetes, preeclampsia, placental vasculopathy, intrauterine growth restriction, and twin gestation that may compromise fetal cerebral perfusion (Table 20.2; see Chapter 13). In one series, such factors were present in approximately one third of cases of intrapartum asphyxia.30 Indeed, “perinatal asphyxia” was identified in 27% of infants of diabetic mothers, and its occurrence correlated closely with diabetic vasculopathy (nephropathy) and presumed placental vascular insufficiency.33 In a more recent cohort of infants that received therapeutic

TABLE 20.1 Timing of Insults Leading to HypoxicIschemic Encephalopathy Of 245 infants who had an MRI scan after neonatal neurological signs (“neonatal encephalopathy”), and evidence of intrapartum perinatal asphyxia: 197 (80%) had MRI evidence of acute peripartum lesions consistent with hypoxic-ischemic insult; only 8 (4%) also had MRI evidence of antenatal injury 40 (16%) had normal MRI scans 8 (4%) had other disorders (e.g., neuromuscular or metabolic diseases) MRI, Magnetic resonance imaging. Data from Cowan F, Rutherford M, Groenendaal F, et al. Origin and timing of brain lesions in term infants with neonatal encephalopathy. Lancet. 2003;361:736–742.

TABLE 20.2  Antepartum/Maternal Clinical Factors Associated With Neonatal Encephalopathy

Antepartum/Maternal

a

Hypothyroidism Obesity Diabetes (particularly pregestational) Fetal growth restriction <5% Hypertension Clinical chorioamnionitis

Dependent on geographical cohort. HIE, Hypoxic-ischemic encephalopathy.

FREQUENCY IN GENERAL POPULATION (%)

FREQUENCY IN HIE POPULATION (%)

0.5713 10–25714 0.5–2715 5 3–5716 1–4717

3 15–50a 5–20a 10–15 5–15 5–10

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hypothermia (n = 98), the frequency of pregestational diabetes and preeclampsia were significantly higher (threefold to fivefold) in women with infants requiring cooling.9 Regarding intrauterine growth restriction, in the largest North American series of neonatal encephalopathy, collected by the Vermont Oxford Registry, 16% of infants were defined as less than the 10th% for weight.5 In a major controlled study of neonatal encephalopathy, 16% of infants with neonatal encephalopathy were growth-restricted compared to only 1.2% of term infants without encephalopathy. Growth restriction was the strongest predictor of neonatal encephalopathy examined, associated with a 30-fold increase in risk.26 In a regional study of moderate or severe neonatal encephalopathy in term infants, 17% were small for their gestational age.8 The additional stress of labor would be expected to compromise placental blood flow. Similarly, impaired placental function and an increased risk of perinatal asphyxia in the infant with intrauterine growth restriction are recognized and appear to account for some of the increased risk of subsequent neurological disability in such infants.34-41 In the most recent series of infants receiving hypothermia, infant birthweight below the 5th percentile for gestational age was significantly associated with the need for therapeutic hypothermia.9 Other factors (e.g., dysmorphic syndromes, severe undernutrition, infection) may also lead to increased risk of neurological disability in intrauterine growth restriction.38,42-46 Moreover, studies in fetal and neonatal animals suggest that the mechanisms for the increased vulnerability of the growth-restricted fetus relate not only to placental insufficiency but also to diminished glucose reserves in the heart, liver, and brain, and to impaired capability to increase substrate supply to the brain with the hypoxic stress of vaginal delivery.47,48 Other less characterized maternal factors have been recognized as important risk factors for neonatal encephalopathy, although pathogenetic mechanisms remain unclear. One such factor is maternal hypothyroidism. In four prospective studies, an elevated risk of up to 10-fold was found for maternal hypothyroidism in infants with neonatal encephalopathy (see Table 20.2).5,7,26,49 Further, maternal drug use can impair the transition of infants after delivery, and infants can display abnormal neurological signs that can mimic neonatal encephalopathy. The details of these agents are outlined in Chapter 38. Although the particular importance of intrauterine hypoxic-ischemic injury, especially intrapartum asphyxia with or without antepartum predisposing factors, in the genesis of the clinical syndrome of neonatal HIE is apparent, most infants who experience intrapartum hypoxic-ischemic insults do not exhibit overt neonatal neurological features or subsequent neurological evidence of brain injury.a The severity and duration of the hypoxic-ischemic insult is obviously critical. The elegant studies of Low16,17,50 and others51,52 demonstrate a striking relationship among the severity and duration of intrapartum hypoxia, assessed by the use of fetal acid-base studies (see Chapter 17), the subsequent occurrence of a neonatal neurological syndrome, and later neurological deficits. Current data suggest that approximately 10% of all term deliveries require some resuscitation with 1% requiring extensive resuscitation,56,57 Of the latter. only 1 to 3 per 1000 will develop signs of evolving encephalopathy consistent with HIE.31,55,58,59 a

References 2, 11, 12, 23, 25, 27, and 50-55.

NEUROLOGICAL SYNDROME The neurological syndrome that accompanies serious peripartum hypoxic-ischemic cerebral injury is the prototype for neonatal HIE. In considering the nature and timing of hypoxia-ischemia as the etiology of neonatal HIE, we consider three features to be important: (1) evidence of fetal distress and/or fetal risk for hypoxia-ischemia (e.g., fetal heart rate (FHR) abnormalities, sentinel event, fetal acidemia); (2) the need for resuscitation and/or low Apgar scores; and (3) an overt neonatal neurological syndrome in the first hours or day of life. Although not discussed here in depth, important systemic abnormalities, presumably related to ischemia, often accompany the neonatal neurological syndrome. The relative frequencies of manifestations of organ injury in term infants with evidence of asphyxia have been investigated in several studies.53,54,60-64 The findings varied as a function of the severity of asphyxia and the definitions of organ dysfunction. In combined data from two reports (Table 20.3),54,60 approximately 20% of infants with apparent fetal asphyxia had no evidence of organ injury. Evidence of involvement of the central nervous system occurred in 62% of infants. Indeed, in 16% of infants, involvement of only the nervous system was apparent. The order of frequency of systemic organ involvement overall has been hepatic > pulmonary > renal > cardiac. In an autopsy series, cardiac involvement was the most common among affection of systemic organs.65 With careful electrocardiographic and enzymatic studies of living infants after perinatal asphyxia, evidence of myocardial ischemia has been commonly observed.66 Representative data from a well-studied series of 144 infants with moderate-severe encephalopathy, found that all infants displayed some form of organ dysfunction, with pulmonary and hepatic approximately 85%, renal 70%, and cardiac 60%.64 These frequencies may relate, in part, to the nature of the diagnostic categories for these abnormalities, but confirm that multiorgan dysfunction is very common in the setting

TABLE 20.3 Manifestations of Organ Injury in Term Asphyxiated Infantsa ORGAN None CNS only CNS and one or more other organs Renal & cardiac approx. 65%: Pulmonary & liver approx. 85% Other organ(s), no CNS a

PERCENTAGE OF TOTAL 0–36 0–36 46–100 10–20

Cumulative total of 107 term infants; definition of asphyxia in both series included umbilical cord arterial pH < 7.2. CNS, Central nervous system. Data from Perlman JM, Tack ED, Martin T, et al. Acute systemic organ injury in term infants after asphyxia. Am J Dis Child. 1989;143:617–620; Martin-Ancel A, Garcia-Alix A, Gaya F, et al. Multiple organ involvement in perinatal asphyxia. J Pediatr. 1995;127:786–793; Shah P, Riphagen S, Beyene J, Perlman M. Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2004;89(2):F152–F155; Phelan JP, Ahn MO, Korst L, Martin GI, Wang YM. Intrapartum fetal asphyxial brain injury with absent multiorgan system dysfunction. J Matern Fetal Med. 1998;7(1):19–22.

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TABLE 20.4  Standardized Scoring Systems for Neonatal Encephalopathy SCORING SYSTEM

PURPOSE/UTILITY

Sarnat

Prognosis applied in first 7 days

14

Modified Sarnat Thompson

Prognosis applied in first 7 days Prognosis applied in first 7 days

5 6

NICHD

Selection in first 6 h of life of moderate-severe NE for hypothermia Defining mild, moderate, and severe NE in first 6 h of life

9

SIBEN

NUMBER OF ELEMENTS

10

ELEMENTS Alertness, tone, posture, reflexes, myocolonus, suck, Moro, oculovestibular, tonic neck, pupils, heart rate, secretions, GI motility, seizures, EEG Alertness, tone, suck, Moro, seizures Alertness, tone, respiratory status, reflexes, seizure, feeding method Alertness, spontaneous activity, posture, tone, suck, Moro, pupils, heart rate, respirations Alertness, spontaneous activity, posture, tone, suck, Moro, pupils, heart rate, respirations, seizures

EEG NECESSARY Yes

No No No No

EEG, Electroencephalography; GI, gastrointestinal; NE, neonatal encephalopathy; NICHD, National Institute of Child Health and Human Development; SIBEN, Score of the Iberoamerican Society of Neonatology.

of moderate-severe peripartum HIE and should be sought by appropriate diagnostic studies. Defining the neurological syndrome of HIE by clinical evaluation is important. Central to this definition is awareness of the characteristics of the normal neurological examination (see Chapter 9). The abnormal features of the examination in infants with HIE were discussed in previous editions of this book and in Chapter 9. To improve interobserver reliability, standardized scores have been developed, and have proven useful in large-scale clinical research studies (see later) (Table 20.4)67-69 The initial neurological examination classification systems developed evaluated infants over the first week of life to define the severity of their encephalopathy for prognostication. The first of these scoring systems was that developed by Sarnat, which was based on serial examinations of 21 term-born infants over the first few weeks of life.70 Three clinical stages of “postanoxic encephalopathy” were described. Stage 1 lasted less than 24 hours and was characterized by hyperalertness, uninhibited Moro and stretch reflexes, sympathetic effects, and a normal electroencephalogram. Stage 2 was marked by obtundation, hypotonia, strong distal flexion, and multifocal seizures. The electroencephalography (EEG) showed a periodic pattern sometimes preceded by continuous delta activity. Infants in stage 3 were stuporous, flaccid, and their brain stem and autonomic functions were suppressed. The EEG was isopotential or had infrequent periodic discharges. Infants who did not enter stage 3 and who had signs of stage 2 for less than 5 days appeared normal in later infancy. Persistence of stage 2 for more than 7 days, or failure of the EEG to revert to normal, was associated with later neurologic impairment or death. This classification system was then further simplified, to be known as the Modified Sarnat score (see Table 20.4). The next scoring system developed for prognostication in neonatal encephalopathy was the Thompson Encephalopathy Score, developed in 1997 (see Table 20.4).68 This scoring system was simpler to apply and did not require EEG to increase its widespread applicability. The initial evaluation showed a good

correlation between the maximal score in the first 7 days of life and neurodevelopmental outcome at 18 months in 44 infants with neonatal HIE. It is important to note that both the Sarnat and the Thompson scoring systems aimed to define neonatal neurological signs during the first week of life to improve the prediction of subsequent neurological deficits. However, as the era of neuroprotection emerged, it became apparent that a standardized neonatal neurological examination tool to be applied in the first few hours of life would be necessary to define eligibility for randomized controlled trials, such as therapeutic hypothermia. For some of the latter trials, the modified Sarnat and Thompson scales were used. For the largest North American study, a new scoring system was developed: the NICHD (National Institute of Child Health and Human Development) Neonatal Encephalopathy Scoring System (see Table 20.4).71 The aim of this scoring system was to identify infants with moderate-severe encephalopathy who were eligible for entry into the trial within the first 6 hours of life. There was recognition that the examination could evolve over the first day of life, as described by Sarnat and Thompson (see temporal evolution of the neurological syndrome later). To further refine the NICHD scoring system by the addition of a mild encephalopathy grouping, the HIE Score of the Iberoamerican Society of Neonatology (SIBEN) was developed in 2016 and involved the assessment of 10 clinical aspects that could be undertaken from immediately after delivery room resuscitation (see Tables 20.4 and 20.5).72 The recognition of mild encephalopathy is of great relevance as it is recognized that at least 40% of hypoxic-ischemic cerebral injury presents as mild disease (see later).59 To classify HIE as mild, moderate, or severe, each item evaluated varies according to the degree of severity (see Table 20.5). With this scoring system, a point is given to every item that corresponds to a level in the SIBEN score, with the diagnosis of HIE considered in the presence of three points or more. This scoring system has been evaluated in clinical practice in Brazil, but it remains under ongoing investigation for its utility in application to the evaluation of all infants requiring resuscitation who may benefit from therapeutic hypothermia. It remains the only current published

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TABLE 20.5  SIBEN Neurological Score Level of consiousness Spontaneous activity Posture Tone Suck Moro Pupils Heart rate (HR) Breathing Seizures

MILD

MODERATE

SEVERE

Hyperalert Normal Mild distal flexion Normal Weak Strong Mydriasis Tachycardia Spontaneous Absent

Lethargy Decreased Marked distal flexion Hypotonia Weak or absent Weak Miosis Bradycardia Periodic Present—Frequent

Stupor/Coma Not present Decerebrate Flaccidity Not present Not present Diverted/nonreactive Lack of HR variability Apnea Present—infrequent

SIBEN, Score of the Iberoamerican Society of Neonatology.

TABLE 20.6 Clinical Features of Severe HIE: Birth to 12 Hours Depressed level of consciousness: usually deep stupor or coma Ventilatory disturbance: “periodic” breathing or respiratory failure Intact pupillary responses Intact oculomotor responses Hypotonia, minimal movement > hypertonia Seizures HIE, Hypoxic-ischemic encephalopathy.

scoring system to include the evaluation of all three grades of neonatal encephalopathy in the first 6 hours of life.

Temporal Evolution of the Neurological Syndrome The temporal evolution of the neurological syndrome in the era before therapeutic hypothermia has been outlined in detail in previous editions of this book. This evolution is most readily apparent in severely affected infants. With less severe forms of HIE changes in the clinical syndrome may be less stereotyped, and thus careful serial clinical evaluation every hour over the first 6 to 12 hours of life may be more sensitive to the evolution. With regard to the most severe form of neonatal encephalopathy, occurring in 20% of HIE,59 a clear evolution has been documented. Although the temporal evolution of the neurological syndrome is more complex in the infant undergoing therapeutic hypothermia because of sedation and response to hypothermia, the principles remain unchanged. In the first hours after the insult, signs of presumed bilateral cerebral hemispheral disturbance predominate (Table 20.6).73,74 The severely affected infant is either deeply stuporous or in coma (i.e., not arousable and minimal, or no response to sensory input). Periodic breathing, or respiratory irregularity akin to this pattern, is prominent, which may be considered as a form of respiratory disturbance as a neonatal counterpart of Cheyne-Stokes respiration, which is observed in older children and adults with bilateral hemispheral disease. In one series, approximately 80% of infants with severe neonatal encephalopathy had abnormal breathing patterns, particularly periodic breathing.75 Those most severely affected may exhibit

marked hypoventilation or apnea. Pupillary responses to light are intact, spontaneous eye movements are present, and eye movements with the oculocephalic response (doll’s eyes maneuver) are usually full. (Pupillary size is variable, although dilated reactive pupils tend to predominate in the less affected infants, and constricted reactive pupils are common in the more severely affected infants.70) Commonly, disconjugate eye movements are apparent. However, only in a few babies are eye signs of major brain stem disturbance seen. Fixed, midposition, or dilated pupils and eye movements fixed to the doll’s eyes maneuver and to cold caloric stimulation are unusual at this stage. If either of these signs is evident at this time, especially in the full-term infant, injury to the brain stem is likely. Most infants at this stage are markedly and diffusely hypotonic with minimal spontaneous or elicited movement. Less severely affected infants have a preserved tone. Others exhibit an increased tone, especially with prominent involvement of the basal ganglia. Clinical seizure-like activity often occurs by 6 to 12 hours after birth in approximately 50% to 60% of the infants who ultimately have seizures.24,55,76 (This early onset of seizures is unlike the later onset, 19 to 28 hours, in infants with neonatal arterial ischemic stroke [see Chapter 21].) A major challenge occurs in the correct clinical recognition of seizures. In one recent study of staff observing high-risk newborns, only 9% of 526 electrographic seizures were identified by clinical observation, indicating an underdiagnosis of seizures. In addition, 78% of 177 nonictal events were incorrectly identified as seizures, indicating an overdiagnosis of seizures.77 Problematically, the more difficult to diagnose seizure types tend to occur more often than the more readily diagnosed seizure types in newborns. A study of 61 seizures in 24 newborns classified seizures by their most prominent clinical features. Clonic and tonic seizures, which might be more readily identified, only occurred in 20% and 8%, respectively, while orolingual, ocular, and autonomic features, which might be more difficult to identify, were the main features in 55%.78 These clinical features contrast with the high frequency of focal clonic seizures in infants with neonatal arterial ischemic stroke (see Chapter 21). Thus, neonatal seizures in the setting of HIE are frequently subtle or clinically invisible. More recent studies using EEG in the assessment of infants with moderate-severe HIE and undergoing therapeutic hypothermia identified the median timing of onset of EEG seizure activity at 13 hours (interquartile

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy

TABLE 20.7 Clinical Features of Severe HIE: 12–24 Hours

TABLE 20.8 Clinical Features of Severe HIE: 24–72 Hours

Variable change in level of alertness More seizures Apneic spells Jitteriness Weakness Proximal limbs, upper > lower (full term) Hemiparesis (full term) Lower limbs (premature)

Stupor or coma Respiratory arrest Brain stem oculomotor and pupillary disturbances

HIE, Hypoxic-ischemic encephalopathy.

range [IQR]: 11 to 22 hours), with maximal seizure burden at a median of 19 hours (IQR: 12 to 29 hours).79 From approximately 12 to 24 hours, the infant’s level of consciousness changes in a variable manner (Table 20.7). Infants with severe disease remain deeply stuporous or in a coma. Infants with less severe disease may often begin to exhibit some degree of improvement in alertness. A recent report from Biselele et al. serially examined 21 infants with evidence of hypoxic-ischemic insult and found that in the first hour 70% of the infants that displayed neurological signs scored greater than 7 on the Thompson scale (see earlier), thereby permitting entry into therapeutic hypothermia; while at 6 hours only 20% of infants scored at this level.80 The authors warn that this “apparent” improvement may prevent infants that need to receive therapeutic hypothermia from being eligible, if their examination is delayed to close to 6 hours of life. Thus, it is regarded that in many of these infants, this improvement is more apparent than real, because the appearance of alertness may not be accompanied by visual fixation or following, habituation to sensory stimulation, or other signs of cerebral function. The notion of apparent rather than real improvement in such cases is supported further by the occurrence at this time of seizures (as noted earlier, median occurrence at 13 hours), apneic spells, jitteriness, and weakness. Apneic spells appear in approximately 50% of infants (65% in one series).11,12,75 Jitteriness develops in about one-fourth of infants and may be so marked that the movements are mistaken for seizures. Distinction can usually be made at the bedside (see Chapter 9). Infants with involvement of basal ganglia may exhibit an increase in their hypertonia, especially in response to handling. Many infants manifest definite, albeit not marked, weakness (see Table 20.7). Although precise correlation is often difficult, these infants appear from the clinical circumstances surrounding their insult to have sustained particularly marked ischemic insults. Full-term infants most often exhibit weakness in the hip–shoulder distribution, with more impressive involvement usually of the proximal extremities. Distinct asymmetry of these latter motor findings is unusual to elicit at this time, although a few full-term infants do exhibit weakness that is confined to or is clearly more severe on one side than on the other. Between approximately 24 and 72 hours, the severely affected infant’s level of consciousness often deteriorates further, and deep stupor or coma may ensue (Table 20.8). Respiratory arrest may occur, often after a period of irregularly irregular (“ataxic”) respirations. Brain stem oculomotor

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HIE, Hypoxic-ischemic encephalopathy.

TABLE 20.9 Clinical Features of Severe HIE: After 72 Hours Persistent, yet diminishing stupor Disturbed sucking, swallowing, gag, and tongue movements Hypotonia > hypertonia Weakness Proximal limbs, upper > lower Hemiparesis HIE, Hypoxic-ischemic encephalopathy.

disturbances are now more common. These usually consist of skew deviation and loss of responsiveness of the eyes to the doll’s eyes maneuver and to cold caloric stimulation. (Rarely, ocular bobbing may appear.) Pupils may become fixed to light in the mid or dilated position. Reactive but constricted pupils are more common in less severely affected infants. Babies who die with HIE most often do so at this time, particularly if the criterion is “brain death.”81 In one large series of infants who died after perinatal asphyxia and HIE, the median age of death was 2 days.65 The cause for the apparent delay in progression to brain death until this period is not known definitely, but delayed cell death has been documented in in vivo models and in neurons in culture (see Chapters 13, 18, and 19). The importance of excitatory amino acids, calcium-mediated deleterious metabolic events, and free radical production has been detailed in Chapter 13. Indeed, studies by MR spectroscopy in the asphyxiated human infant (see later) have documented a delayed deterioration of cerebral energy state. However, although delayed cell death most probably accounts for this clinical deterioration, consideration should also be given to the occurrence of frequent subclinical electrical seizures as the reason for the deterioration. Although EEG is required for this determination, the potential effectiveness of anticonvulsant therapy warrants the procedure. Infants who survive to greater than 72 hours will at this point usually improve over the next several days to weeks; however, certain neurological features persist (Table 20.9). Although the level of consciousness improves, often dramatically, mild to moderate stupor continues. Disturbances of feeding are extremely common and relate to abnormalities of sucking, swallowing, and tongue movements. The power and coordination of the muscles involved (innervated by cranial nerves V, VII, IX, X, and XII) are deranged. A few infants require tube feedings for weeks to months, particularly those with involvement of deep nuclear gray matter and brain stem (see Prognosis). In the large series studied by Brown and co-workers,11,12 80% of infants required early tube feedings

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because of feeding difficulty. Generalized hypotonia of limbs is common, although hypertonia, particularly with the passive manipulation of limbs, is frequent on careful examination, especially among infants with prominent involvement of basal ganglia. The patterns of weakness discussed in the previous section become more readily elicited, although the weakness is rarely marked.

DIAGNOSIS The recognition of neonatal HIE depends principally on information gained from a careful history and a thorough neurological examination. The contributing role of certain metabolic derangements requires evaluation. Determination of the site or sites and extent of the injury is made by the history, neurological examination, EEG, and neuroimaging studies (ultrasonography, MRI).

History Recognition of neonatal HIE requires awareness of those intrauterine situations that account for most cases. Thus, information should be sought regarding maternal disorders with an increased risk for peripartum HIE (see Table 20.2) and that could lead to uteroplacental insufficiency and disturbances of labor or delivery that could impair placental respiratory gas exchange or fetal blood flow. The value of fetal evaluation including electronic fetal monitoring, particularly when supplemented by fetal blood sampling to determine acid-base status, is discussed in Chapter 17.

Neurological Examination Recognition of the neurological signs outlined previously provides critical information concerning the presence, site, and extent of hypoxic-ischemic injury in the newborn infant. The neurological examination plays two critical roles. First, the systematic neurological examination in the first 6 hours of life may allow recognition by the clinician of the presence and severity of any neonatal HIE. This is essential to allow that infant to be eligible for potentially neuroprotective strategies, such as therapeutic hypothermia. Second, the regular and systematic neurological examination of the infant with encephalopathy over the first week of life carries very important information for establishing a prognosis (see the section on prognosis).

Metabolic Parameters Certain metabolic derangements may contribute significantly to the severity and qualitative aspects of the neurological syndrome, and the diagnostic evaluation should include evaluation of such derangements. Hypoglycemia, hyperammonemia, hypocalcemia, hyponatremia (inappropriate secretion of antidiuretic hormone [ADH]), hypoxemia, and acidosis are among the metabolic complications that may occur, often because of associated disorders, and that may exacerbate certain neurological features or add new ones. Of particular interest in this context is the occurrence of hypoglycemia and its potential role in the accentuation of brain injury. In a detailed study of 185 infants with evidence of intrauterine asphyxia (cord pH < 7.00), fully 15% exhibited blood glucose concentrations lower than 40 mg/dL in the first 30 minutes of life.82 The hypoglycemia may relate, in large part, to enhanced anaerobic glycolysis and, therefore, glucose use, in

an attempt to preserve cellular energy levels (see Chapter 13). By multivariate analysis, the odds ratio (OR) for an abnormal neurological outcome was 18.5 when infants with blood glucose levels lower than 40 mg/dL were compared with those with levels higher than 40 mg/dL. These data may have important implications for management (see later). Hyperammonemia may occur in newborns with severe perinatal asphyxia.83 Although very uncommon, levels of approximately 300 to 900 µg/mL have been detected in the first 24 hours of life and are usually accompanied by elevated serum glutamic oxaloacetic transaminase levels. Clinical correlates may be difficult to distinguish from those secondary to HIE, although hyperthermia and hypertension have been frequent additions in patients with hyperammonemia. Clinical improvement is coincident with falling blood ammonia levels. The pathogenesis of the hyperammonemia is unclear, although a combination of increased protein catabolism, secondary to hypoxic “stress,”84 and impaired liver function, and therefore hepatic urea synthesis, is a good possibility (see Chapter 27). Recall that hepatic disturbance is a common feature of the systemic multiorgan dysfunction observed with intrauterine asphyxia (see earlier). Other metabolic parameters have been studied and some may hold promise as measures of severity of the hypoxic-ischemic insult (Table 20.10), although currently the precise sensitivity and specificity of these determinations require further study before general use is warranted. The metabolites and markers are best considered in terms of their relevance to energy metabolism, excitatory amino acids, free radical metabolism, inflammation, brain-specific proteins, and compounds from other organ systems that may have sustained hypoxic-ischemic injury (see Table 20.10). Thus, the early clinical detection of blood or cerebrospinal fluid (CSF) biomarkers might allow an earlier diagnosis compared with neuroimaging. This identification would allow the earlier initiation of intervention measures to improve neonatal survival and reduce the degree of brain injury. In summary, such biomarkers could be important for diagnosis of neonatal HIE, selection of intervention, determination of efficacy, as well as assessment of the severity of illness and the estimation of prognosis. Concerning energy metabolism, perinatal asphyxia has been associated with hypoglycemia, elevated lactate in blood and CSF, elevated lactate/creatinine (L/C) ratio in urine, and elevated lactate and hydroxybutyrate dehydrogenases in CSF.82,85-88 Of these, the value of detection of early hypoglycemia was discussed earlier. Of particular interest is the ratio of L/C in urine. In a study of 40 infants with evidence of intrapartum asphyxia, the mean (±SD) ratio within 6 hours of life was 16.8 ± 27.4 in the asphyxiated infants who subsequently developed the clinical features of HIE versus 0.2 ± 0.1 in those who did not develop encephalopathy, and 0.09 ± 0.02 in normal infants.87 Moreover, the ratio was significantly higher in the infants who had neurological sequelae at 1 year (25.4 ± 32.0) than in those with favorable outcomes (0.6 ± 1.5). The degree of elevation of lactate in blood at 30 minutes of life also may be a useful predictor of the severity of perinatal asphyxia.88 A more recent study of L/C in urine by proton nuclear MR spectroscopy within 6 and 24 hours after birth in 50 normal infants and 50 infants with asphyxia who developed HIE showed that the L/C ratio was elevated among asphyxiated neonates in the first 6 hours after birth to 11-fold greater than in normal

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy

TABLE 20.10 Potential Adjunctive Determinations in Blood, Urine, or Cerebrospinal Fluid in Assessment of Perinatal Asphyxiaa DETERMINATION Energy metabolism Glucose Lactate Lactate/creatinine ratio Lactate dehydrogenase Excitatory amino acids Glutamate Aspartate Glycine Free radical metabolism Hypoxanthine Uric acid Nonprotein-bound iron Protein carbonyls Isoprostanes Ascorbic acid Arachidonate metabolites Nitric oxide Antioxidant enzymes Inflammatory markers Interleukin-6 Interleukin-10 Interleukin-1 beta Tumor necrosis factor-alpha Brain-specific proteins Neuron-specific enolase Neurofilament protein Protein S-100 Glial fibrillary acidic protein Creatine kinase-BB Other Erythropoietin Nerve growth factor Cyclic adenosine monophosphate

BODY FLUID Blood Blood, CSF Urine CSF CSF CSF CSF Blood, urine Blood, urine Blood CSF CSF CSF CSF Blood, CSF CSF Blood, CSF CSF Blood Blood, CSF Blood, CSF CSF Blood, urine, CSF Blood, CSF Blood, CSF Blood CSF CSF

a

See text for references. CSF, Cerebrospinal fluid.

neonates (P = .0001).89 This ratio decreased to 1.5 ± 0.55 for asphyxiated cases over the first 24 hours after birth, fivefold greater than in the control group (P = .0001). The severity of asphyxia correlated with the greater L/C ratio among cases (P = .0007). The sensitivity and specificity of the L/C ratio were 96.1% and 100%, respectively. This measure is not yet used in routine clinical practice for the detection or confirmation of HIE. Concerning excitatory amino acids, elevations of the excitotoxic amino acids glutamate, aspartate, and glycine (through the N-methyl-d-aspartate [NMDA] receptor) have been observed in CSF in the first day of life (see Table 20.10).90-94 Correlations with severity of HIE have been shown. Clinical observation showed increased levels of serum glutamate after neonatal HIE insult.95,96 Within 24 hours, the increase of glutamate was significant, and reached a peak at day 3 of postnatal life. At day 7 (recovery period) the levels returned to normal, and serum glutamic acid concentrations were closely related to the severity of HIE.97

517

Concerning free radical metabolism, many studies support the involvement of reactive oxygen and nitrogen species in the final common pathway to cell death with neonatal HIE (see Table 20.10).98-115 These studies have shown elevations in sources of free radicals (e.g., hypoxanthine, non-protein-bound iron, arachidonate metabolites), indicators of lipid peroxidation (e.g., isoprostanes) or oxidized proteins (e.g., protein carbonyls), and markers of free radical use (e.g., ascorbic acid, antioxidant enzymes). Of particular note in clinical studies is superoxide dismutase (SOD), an antioxidant enzyme that removes the oxygen free radical, superoxide, to protect cells from free radical damage (see Chapter 13). Its activity level reflects the oxygen free radical scavenging capacity. Glutathione peroxidase, a second key antioxidant enzyme, detoxifies hydrogen peroxide, the product of action of SOD. In addition, also frequently studied is the lipid peroxidation product of free radical activity, malondialdehyde (MDA), which reflects the extent of oxidative damage to cells. Thus, excess free radicals consume SOD, produce a large amount of MDA, promote the release of inflammatory factors in brain tissue, induce nerve cell apoptosis, and increase permeability of the blood-brain barrier in neonatal HIE.116 A study of 50 cases of asphyxiated full-term newborns found that serious asphyxia resulting in the death of newborns with HIE was associated with concentrations of MDA and glutathione peroxidase in plasma and CSF that were significantly higher than in infants who survived.117 In neonatal HIE with epilepsy, serum MDA concentrations were significantly higher than in HIE without seizures.118 Moreover, serum MDA concentrations were increased with the degree of brain injury, which was confirmed by imaging analysis. 119 Clinical studies found that in the acute stage of HIE, serum SOD concentrations were significantly decreased compared to those of a healthy control group, and MDA concentrations were significantly increased.120 Concerning inflammatory markers, related potentially to hypoxic-ischemic or intrauterine infection or both, elevations of certain cytokines (interleukin [IL]-6, IL-10, IL-1beta, IL-18, ICAM-1, P-selectin, and tumor necrosis factor-alpha) have been documented in blood and CSF in both term and preterm infants (see Table 20.10).121-127 The degree to which the elevations in cytokines are primary or secondary is unclear (see Chapter 13). A recent review of the role of inflammation in the exacerbation and recovery from hypoxic-ischemic injury outlines the key mediators.128 Concerning brain-specific proteins, specific components of neurons (neuron-specific enolase, neurofilament protein, creatine kinase-BB [CK-BB]) and astrocytes (S-100, glial fibrillary acidic protein, CK-BB) have been studied in blood and CSF to detect evidence of neuronal and glial injury.127,129-154 In general, elevations of these markers in blood or CSF in the first hours of life after perinatal asphyxia have correlated approximately with the severity of clinical and brain imaging findings. However, the value of studies of blood is tempered somewhat by the finding of S-100 and neuron-specific enolase (NSE) in placenta; this suggests that these molecules are not entirely brain specific.148 A recent study of infants receiving hypothermia treatment for neonatal HIE demonstrated abnormal changes in blood NSE that correlated with brain injury on neuroimaging.155 However, findings in relation to the severity of the injury remain variable. Available data suggest that the determination of CK-BB is a very sensitive indicator of brain disturbance.132,134-140,145,150,151

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However, the extreme sensitivity of the indicator in blood impairs the specificity of the measure because variable but appreciable proportions of infants with elevated concentrations of CK-BB in cord blood or neonatal blood samples have no evidence of irreversible brain injury and have a normal neurological outcome. However, two studies of the concentrations of CK-BB in CSF suggested greater specificity as well as sensitivity concerning identification of hypoxic-ischemic brain injury than with determination of blood CK-BB concentrations (see Table 20.10).140,145 Concerning other markers, elevations of erythropoietin in blood and nerve growth factor and cyclic adenosine monophosphate in CSF have been documented after perinatal asphyxia (see Table 20.10).156-159 The value of these markers and the significance of their elevations remain to be established. Currently, none of the markers has been established to be of sufficiently high sensitivity and specificity to be appropriate for general clinical use. However, several appear to be promising (see Review.)127

Lumbar Puncture A lumbar puncture should be performed on any infant with HIE in whom the diagnosis is unclear. It is particularly important to rule out other potentially treatable intracranial disorders (e.g., early-onset meningitis) that may mimic the clinical features of HIE.

Electroencephalogram The EEG changes in HIE may provide valuable information concerning the severity of the injury.70,160-189 Although a considerable variety of tracings may be observed, the most common evolution of EEG changes in severe HIE is depicted in Fig. 20.1. The initial alteration is voltage suppression and a decrease in the frequency (i.e., slowing) into the delta and low theta ranges. Within approximately 1 day, and often less, an excessively discontinuous pattern appears, characterized by periods of greater voltage suppression interspersed with bursts, usually asynchronous, of sharp and slow waves. Some infants exhibit multifocal or focal sharp waves or spikes at this time, often with

Amplitude (suppression) and frequency

Periodic pattern and/or multifocal or focal sharp activity

Periodic pattern with fewer bursts and more voltage suppression

Isoelectric Figure 20.1  Evolution of the electroencephalographic changes in severe hypoxic-ischemic encephalopathy. See text for temporal aspects.

a degree of periodicity. Over the next day or so, the excessively discontinuous pattern may become very prominent, with more severe voltage suppression and fewer bursts, now characterized by spikes and slow waves. This burst-suppression pattern is of ominous significance, especially in the full-term infant (see Chapter 10). However, it is critical to recognize that excessively discontinuous patterns with prolonged interburst intervals (IBIs), which are not as severe as classic burst-suppression patterns, nevertheless also are associated with an unfavorable outcome (see the later section on prognosis and Chapter 10). Indeed, in one large series of infants, only 16% of excessively discontinuous tracings (in patients with a generally unfavorable outcome) exhibited burst-suppression patterns by classic definition.190 Notably, however, as many as 50% of asphyxiated term infants with a burst-suppression pattern identified by amplitude-integrated EEG (aEEG) in the first hours of life develop normal or nearly normal tracings within 24 hours (see later).191 In the severely affected infant, the excessively discontinuous EEG may then evolve into an isoelectric tracing and a hopeless prognosis. Caution in the interpretation of apparent isoelectric tracings in the newborn not undergoing hypothermia therapy, especially in the first 10 hours of life, is indicated by the findings of Pezzani and co-workers,169 which showed that of 17 asphyxiated newborns with isoelectric or “minimal” background activity in the first 10 hours, one was normal and one exhibited only epilepsy on follow-up (15 of the 17 died in the neonatal period). In general, those asphyxiated infants whose EEG tracings revert to normal within approximately 1 week have favorable outcomes.70,191 aEEG is a commonly applied method for continuous monitoring of electrical activity in the newborn (see Chapter 10)192 and has considerable value in the assessment of the encephalopathic term newborn (Fig. 20.2).191-197 This approach has been crucial in the selection of infants for treatment with mild hypothermia (see later). The most useful tracings for detection of severe encephalopathy have been continuous low-voltage, flat, and burst-suppression tracings. Positive predictive values (PPVs) for an unfavorable outcome with such tracings in the first hours of life are 80% to 90% (see the later section on prognosis). Of infants with these marked background abnormalities, 10% to 50% may normalize within 24 hours. Rapid recovery is associated with a favorable outcome in 60% of cases. Although the aEEG acquired within the first 6 hours of age has been considered one of the best predictors of neurological outcome at 18 months in infants with neonatal HIE who did not receive hypothermia therapy,198 since the widespread use of hypothermia therapy, the predictive value of early aEEG has changed, and infants have been shown to have a normal neurological outcome if the aEEG background voltage activity recovers by 48 hours.199-201 In a recent meta-analysis of nine studies with 520 infants treated with therapeutic hypothermia for moderate or severe HIE, the predictive value of an abnormal tracing on aEEG, acquired at 6, 24, 48, and 72 hours of age, was examined.202 The authors found that (1) a persistent, severely abnormal aEEG background at 48 hours of age or beyond predicted an adverse outcome (PPV value 85% and diagnostic OR 67 at 48 hours); and (2) at 6 hours of age, the aEEG background in hypothermia-treated infants had a good sensitivity at 96% (95% confidence interval [CI], 89% to 97%) but low specificity at 39% (95% CI, 32% to 45%).

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy

A

B

519

C

Figure 20.2  Term infant born via emergency cesarean section for fetal bradycardia with Apgar scores 1,1 4,5 and 4.10 Seizures began at 3 hours of age. Received therapeutic hypothermia from 3 hours of life. aEEG studies at 3 hours of life (A), day 3 (B), and day 7 (C) present the evolution from a suppressed flat tracing to burst suppression by day 3 and normal amplitude with cyclicity on day 7.

Continuous monitoring of conventional EEG with portable equipment has been found to be particularly useful in the identification of seizure activity (see Chapter 12).171,203 Early detection of the seizures and the evaluation of response to anticonvulsant therapy are facilitated by modern portable monitoring systems. EEG data can assist in the determination of whether clinical events are correlated with electrical seizures requiring anticonvulsant medication or with nonepileptic events in which anticonvulsant medication administration can be avoided. As discussed earlier, some seizures have readily identifiable clinical manifestations (i.e., clonic or tonic components), while many seizures have more subtle manifestations (i.e., orolingual, ocular, or autonomic).78 The most comprehensive guideline on continuous EEG monitoring in the newborn was produced in 2011 by the American Clinical Neurophysiology Society.204 The guideline was created to standardize care and define the best neuromonitoring practices in the neonatal population, while recognizing that not all recommendations would be feasible or applicable across institutions. The guideline recommendations included that (1) electrodes be placed using the International 10 to 20 system with additional electrocardiogram, respiratory, eye, and electromyography leads; (2) at least 1 hour of recording be assessed to adequately assess cycling through wakefulness and sleep; (3) high-risk newborns be monitored for at least 24 hours to screen for the presence of electrographic seizures; and (4) in newborns with seizures, monitoring occur during seizure management and for an additional 24 hours after the last electrographic seizure.204 Video EEG recording was recommended for 24 hours rather than a briefer EEG recording because many newborns will not have seizures in the first hour of recording but will experience electrographic seizures within the first day.205,206 A statement from the American Academy of Pediatrics recommends that centers performing therapeutic hypothermia in newborns with HIE have either aEEG or conventional EEG available for seizure identification.207 This approach provides insight not only into potentially treatable conditions (frequent, clinically silent seizures) but also into the status of the cerebral hemispheres in an infant who is heavily sedated or therapeutically paralyzed.

TABLE 20.11 Most Frequent Correlations of Electroencephalographic Patterns and Table: Topography of Neonatal Hypoxic-Ischemic Brain Injurya

EEG PATTERN Excessive discontinuity, burst suppression, persistent marked voltage suppression, isoelectric EEG pattern Excessive sharp waves: positive vertex or rolandic, positive frontal, and negative occipital sharp waves Focal periodic lateralized epileptiform discharges

TYPE OF HYPOXICISCHEMIC BRAIN INJURY Diffuse cortical and thalamic neuronal necrosis Periventricular leukomalacia (also periventricular hemorrhagic infarction; see Chapters 16 and 24) Focal cerebral ischemic necrosis (infarction)

a

See text for references. EEG, Electroencephalographic.

The type of EEG abnormality may indicate a specific pathological variety of hypoxic-ischemic brain injury (Table 20.11). Diffuse and severe abnormalities (excessive discontinuity with prolonged IBI, burst suppression, marked voltage suppression, isoelectric EEG) are observed most commonly with diffuse cortical neuronal necrosis. Involvement of thalamus may also be important (see Chapter 10).a The particular value of serial EEG in assessment of the asphyxiated infant is pronounced.185,187,209 A single EEG study, particularly during the acute phase of the disease, may suggest a more ominous outcome than do subsequent EEG studies (see Chapter 10).210 Focal periodic epileptiform discharges are

a

References 162, 164-167, 171, 179, 183-188, and 208.

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Unit IV  Hypoxic-Ischemic and Related Disorders

characteristic of focal cerebral infarction211,212; in one series, approximately 90% of infants with such discharges had infarctions (see Chapter 21).211 The role of the EEG in the assessment of brain death in the asphyxiated newborn has not been delineated decisively.81,213-222 Thus, an isoelectric EEG can be observed in infants with cerebral neuronal necrosis but not death of the entire brain (i.e., brain death). Conversely, persistent EEG activity for many days has been documented in infants with clinical and radionuclide evidence of brain death.81,217,218,223 Currently, the guidelines of the Task Force for the Determination of Brain Death in infants between the ages of 7 days and 2 months requires two clinical examinations indicative of loss of all cerebral and brain stem function and two isoelectric EEG tracings carried out according to standardized techniques separated by 48 hours.224 Although data are limited,217,218 a 72-hour observation period for term infants less than 7 days of age appears warranted in most cases and only when the cause of the coma is unequivocally established.

Neuroimaging Evaluation Neuroimaging is used to identify the key neuropathologies, as outlined in Chapter 18. These include: (1) selective neuronal necrosis, including three basic patterns, that is, diffuse injury, cerebral cortex-deep nuclear injury, and deep nuclear-brain stem injury; (2) parasagittal cerebral injury; (3) periventricular leukomalacia (see Chapter 16); and (4) focal ischemic necrosis and stroke (see Chapter 21). The accurate diagnostic application of neuroimaging modalities in the newborn infant with HIE is related to the level of radiological expertise for the acquisition and interpretation of the studies, regardless of the neuroimaging method. The methods of acquisition and level of experience in the interpretation of neuroimaging studies in the newborn can vary greatly between institutions. Integration of neonatal, neuroradiological, and radiological physicians by joint conference and review of case materials on a regular basis (e.g., weekly) will assist in improved communication and the application of modern neuroimaging methods. In addition,

A

expert interpretation at a center of excellence in perinatal and neonatal neurology should be requested.

Cranial Ultrasound Cranial ultrasound remains the most commonly used neuroimaging modality in the neonatal intensive care unit (NICU) setting, and is commonly applied to the term infant with neonatal encephalopathy. In the Vermont Oxford Neonatal Encephalopathy Registry, cranial ultrasound was acquired in nearly 40% of all infants with neonatal encephalopathy on a median of day 4 of life.225 Cranial ultrasound may be the only imaging modality possible if an infant is too clinically unstable to transport from the neonatal intensive care unit. Cranial ultrasound is sensitive for parenchymal hemorrhage, ventricular size, gross brain malformations, and cystic changes in the brain parenchyma (see Chapter 10). It is less sensitive for smaller and more subtle abnormalities within the brain, including cerebral cortical or brain stem neuronal disease, noncystic white-matter abnormalities, and minor cerebral dysgenesis. It is a very useful screening evaluation in the term infant, with encephalopathy; cerebral dysgenesis has been identified in approximately 2% to 4% of infants who had been diagnosed with hypoxic-ischemic injury (Table 20.12). Cranial ultrasound is often used to assess the presence of slit-like ventricles, or sulcal effacement related to cerebral edema, and hemispheric or basal ganglia echodensity. Cranial ultrasound also can detect severe deep nuclear gray matter injury (Figs. 20.3 and 20.4). However, cranial ultrasound lacks sensitivity in defining the full extent of the cerebral lesions, even in severe encephalopathy, and particularly in the first 24 hours of life.226,227 Because of the delay in the evolution of cranial ultrasound abnormalities by a minimum of 48 hours, detection of pronounced abnormalities on the first day of life may assist in identifying established severe HIE originating before the onset of labor.228

Computed Tomography Computed tomography (CT), in medical centers without ready access to MRI, has some value in the initial evaluation of the

B Figure 20.3  Hypoxic-ischemic injury to basal ganglia in a 24-hour-old full-term infant who experienced severe perinatal asphyxia. (A) Coronal ultrasound scan shows marked bilateral echodensities in the region of basal ganglia and thalamus (arrows). The ventricles are not visible. (B) Coronal section of the cerebrum from the same infant, who died at 80 hours of age. Note the bilateral areas of hemorrhagic necrosis, involving the putamen, globus pallidus, and thalamus.

Not recorded None noted

5%

4%

Whitematter injury Other diagnosis

45%

10%

25%

80%

Cortical injury

No abnormality Basal ganglia/ thalamus

6 days (1–24) 30%

14 days of birth 16%

None noted

Not recorded

75% any 65% moderatesevere 58%

10 days

48

Acute sentinel event: umbilical cord prolapsed (19%), uterine rupture (23%), placental abruption (46%)

One of: Apgar score ≤5 at 5 min, pH <7.1, BD >10

173

OKEREAFOR 200810

MILLER 200529

Either fetal heart rate monitoring abnormalities or cord pH <7.1 or delayed respiration or 5-min Apgar <7 or Multiorgan failure 245

COWAN 200328

Arterial infarction in 10%

21%

36%

31%

33%

72 h

15%

45%

33%

40%

14 days

64

4%

84% any 13% severe

63%

80% any 58% moderatesevere

20%

8 days (2–30)

67 no hypothermia

Neonatal encephalopathy and abnormal EEG and cord pH <7.0 or delayed respiration or 10-min Apgar <5, or both

One of: Apgar score ≤5 at 5 min, pH <7.0, BD >10

Neonatal encephalopathy and one of “fetal distress” cord acidemia, 5-min Apgar ≤5, or both

48

RUTHERFORD 2010476

STEINMAN 2009274

CHAU 2009229

2%

25%

15%

30%

18%

7 days

1,074

Seizures or stupor Coma or hypoth­er­ mia or Apgar at 5 min <3

VERMONT OXFORD 2014225

23%

28%

36% moderatesevere

13%

6 days (3–8)

61 no hypothermia

Two of: Apgar score ≤5 Need for mechanical ventilation at 10 min pH <7.0, BD >12

CHEONG 2012477

EEG, Electroencephalographic; MRI, magnetic resonance imaging. From Inder T. Role of Neuroimaging. Chapter 10. In: Neonatal Encephalopathy and Neurologic Outcome, Second Edition. Washington DC, 2014, American College of Obstetrics & Gynecology.

Number of infants Day of MRI scan (range)

Inclusion criteria

STUDY

TABLE 20.12  Neuroimaging Characteristics on Magnetic Resonance Imaging in Term Encephalopathy

11% from total of 555

44% (n = 186) normal or white matter/ cortical See cortical injury

See cortical injury 41%

10 days (2–42)

425

Term neonatal encephalopathy and MRI in first 6 weeks Apgar score ≤5 at 5 min or pH <7.1, or both “fetal distress”

MARTINEZBIARGE 2010 2011275,276

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy 521

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Unit IV  Hypoxic-Ischemic and Related Disorders

A

B Figure 20.4  Perinatal asphyxia. (A) Coronal and (B) parasagittal ultrasound scans in a 1-day-old full-term infant who experienced perinatal asphyxia. In A, note the increased echogenicity in the basal ganglia (putamen) (arrowheads) and the thalamus (arrows). In B, note the increased echogenicity in the region of the thalamus and basal ganglia (arrowheads); the slit-like lateral ventricle is indicated by the arrow for orientation. A computed tomography scan on day 6 (not shown) demonstrated decreased attenuation in the echogenic areas.

TABLE 20.13  Neuroimaging Results Number of infants Day of life at first scan, median (interquartile range) Any reported abnormality Intraventricular hemorrhage Extraaxial hemorrhage Parenchymal hemorrhage Deep nuclear gray matter abnormality Cystic white matter injury Diffuse white matter injury Venous or arterial occlusion Ventriculomegaly Cerebellar injury Brain stem injury Diffuse cortical signal abnormality Parasagittal watershed injury Absent posterior limb of the internal capsule Other abnormality

ULTRASOUND

CT

MRI

2006/4111 (48.8) 2 (1–3); N = 2001 642/1985 (32.3) 171/2001 (8.5) 59/2003 (2.9) 90/2001 (4.5) 140/1994 (7.0) 43/1997 (2.2) — 22/1980 (1.1) 84/2004 (4.2) 21/1986 (1.1) — — — — 329/2000 (16.5)

933/4107 (22.7) 2 (2–3); N = 928 552/930 (59.4) 110/930 (11.8) 321/927 (34.6) 125/929 (13.5) 65/926 (7.0) 24/928 (2.6) — 54/925 (5.8) 39/929 (4.2) 29/929 (3.1) 7/927 (0.8) — — — 190/931 (20.4)

2690/4109 (65.5) 6 (4–8); N = 2682 1798/2676 (67.2) 220/2686 (8.2) 487/2686 (18.1) 292/2687 (10.9) 603/2671 (22.6) 131/2677 (4.9) 628/2674 (23.5) 183/2657 (6.9) 92/2687 (3.4) 137/2677 (5.1) 126/2677 (4.7) 572/2673 (21.4) 285/2665 (10.7) 114/2659 (4.3) 588/2686 (21.9)

Data presented as n/N (%) unless noted otherwise. CT, Computed tomography; MRI, magnetic resonance imaging. Courtesy Barnette AR, Horbar JD, Soll RF, et al. Neuroimaging in the evaluation of neonatal encephalopathy. Pediatrics. 2014;133(6):e1508–e1517.

infant with HIE. As we discuss later, MRI is far preferable. CT does have several useful characteristics, including high sensitivity for the detection of acute hemorrhage and bone abnormalities, a short examination time, and wide availability. These features are useful in the evaluation of acute brain pathology, particularly in the setting of traumatic brain injury. However, in the setting of HIE, MRI is more sensitive, particularly for injury to the cerebral cortex, deep nuclear gray matter, and cerebral white matter. These characteristics are demonstrated by the results from neuroimaging of 1421 term infants with neonatal encephalopathy in the Vermont Oxford

Neonatal Encephalopathy Registry from 2006 to 2008 (Table 20.13). The advantage of MRI, relative to CT, was further demonstrated by a comparison of the same infants undergoing direct imaging comparisons on the same day in this cohort (Table 20.14). Particularly apparent is the superiority of MRI in the diagnosis of deep gray matter injury and cerebral parenchymal injury. These data are consistent with another report comparing CT scans with MRI on day 3 of life in the setting of acute neonatal encephalopathy (Fig. 20.5). In this study of 48 term born infants with HIE, it was noted that the

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy

523

TABLE 20.14  Neuroimaging Findings in Infants With 2 Types of Imaging on the Same Day ULTRASOUND VERSUS CT

ULTRASOUND Intraventricular hemorrhage Extraaxial hemorrhage Parenchymal hemorrhage Subependymal hemorrhage Deep nuclear gray matter abnormality Cystic white matter injury Venous or arterial occlusion Cerebellar injury Brain stem injury

2/43 2/42 5/42 1/42 1/42 0/42 0/42 1/42

(5) (5) (12) (2) (2) (0) (0) (2)

ULTRASOUND VERSUS MRI

CT

4/43 10/43 7/43 2/43 4/42 2/42 1/42 3/43

ULTRASOUND (9) (23) (16) (5) (10) (5) (2) (7)

3/47 1/46 3/46 1/46 4/46 0/46 0/46 0/46

(6) (2) (7) (2) (9) (0) (0) (0)

CT VERSUS MRI

MRI

5/47 11/47 6/47 2/47 11/47 4/47 2/47 4/47

CT (11) (23) (13) (4) (23) (9) (4) (9)

8/70 17/69 10/69 0/69 8/69 1/69 12/69 1/69 6/69

MRI

(11) (25) (14) (0) (12) (1) (17) (1) (9)

9/70 14/70 13/70 1/70 18/70 2/70 13/70 5/70 6/70

(13) (20) (19) (1) (26) (3) (19) (7) (9)

Data presented as n/N (%). CT, Computed tomography; MRI, magnetic resonance imaging. Courtesy Barnette AR, Horbar JD, Soll RF, et al. Neuroimaging in the evaluation of neonatal encephalopathy. Pediatrics. 2014;133(6):e1508–e1517.

*

*

A

B

C

D

E

F

G

H

Figure 20.5  Comparison of computed tomography (CT) versus magnetic resonance imaging (MRI) at day 3 of life in hypoxic-ischemic encephalopathy. CT identifies BN-predominant pattern but not cortical injury. This newborn has the BN-predominant pattern (A to D). The injury in the BN is apparent on CT, MRI, and the apparent diffusion coefficient (ADC) map. Superiorly, a focal stroke (white arrow) in the left parietal lobe, and cortical injury in the paracentral gyri bilaterally (empty white arrows) can be seen on the ADC map (H) as restricted diffusion areas, but are not evident on CT (E). On MRI, these lesions are most readily seen as hyperintensities on T1-weighted imaging (black and empty arrows, F). (Courtesy Chau V, Poskitt KJ, Sargent MA, et al. Comparison of computer tomography and magnetic resonance imaging scans on the third day of life in term newborns with neonatal encephalopathy. Pediatrics. 2009;123:319–326.)

extent of cortical injury and focal-multifocal lesions, such as strokes and white matter injury, was less apparent on CT than MRI, particularly diffusion-weighted MRI (DWI).229 Of particular importance, in addition to its limited diagnostic role, there are increasing concerns regarding the impact of radiation

exposure from CT on the developing brain (i.e., the risk of future malignancy and later cognitive impairments). These concerns are outlined in Chapter 10. Until further data are available, this neuroimaging technique should be restricted to select settings in which the information obtained from the imaging

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TABLE 20.15  Major Techniques for Diagnosis of Specific Neuropathological Types of Neonatal HIE

NEUROPATHOLOGICAL TYPE Selective neuronal necrosis: cerebral cortical Selective neuronal necrosis: basal ganglia and thalamus Selective neuronal necrosis: brain stem Parasagittal cerebral injury Focal and multifocal ischemic brain injury Periventricular leukomalacia

MRI ++ ++ ++ ++ ++ ++

DIAGNOSTIC TECHNIQUE CT

ULTRASOUND

+ + ± + ++ +

– + – – + ++a

a

Very useful for detection of focal component; not useful for detection of diffuse component or “noncystic periventricular leukomalacia” (see text). ++, Very useful; +, useful; ±, questionably useful; –, not useful. CT, Computed tomography; HIE, hypoxic-ischemic encephalopathy; MRI, magnetic resonance imaging.

study is clearly of benefit to the patient and cannot be readily obtained with some other modality. Examples would include infants with severe head trauma at risk for major epidural bleeding and those who require more definitive imaging in a very brief period because of severe clinical instability.

Magnetic Resonance Imaging MRI provides the highest sensitivity for both anatomical and functional detail and also offers an array of imaging options that can be tailored to the specific clinical question (see later). MRI, however, does have some drawbacks compared with other imaging modalities, particularly in the neonatal period. Unlike cranial ultrasound, patients must typically be transported to a radiology suite from the neonatal intensive care unit for MRI, which may pose some risk to those infants who are unstable. Safely imaging encephalopathic neonates is a unique challenge. Studies have shown that at least 20% of term-born infants with severe HIE cannot be safely transported to the MRI scanning suite because of the severity of their illness.230 Further information on MRI in infants and the techniques applied in MRI are detailed in Chapter 10. MRI has been used in a large number of studies of neonatal HIE.28,29,226,231-272 The entire spectrum of hypoxic-ischemic brain injury has been demonstrated (Table 20.15). The major findings by MRI are outlined in Table 20.16. Conventional MRI shows the abnormalities in the first 3 to 4 days, but generally not on the first day. However, DWI, based on the molecular diffusion of water, is not only more sensitive than conventional MRI, but also shows abnormalities earlier, often in the first 24 to 48 hours after birth (see later discussion, Fig. 20.6). The correlates of the MRI findings with the neuropathological states described in Chapter 18 are apparent (Figs. 20.7 to 20.14). Thus, selective cerebral cortical neuronal injury is manifested by loss of the cerebral gray-white matter differentiation and by cortical high signal (highlighting) on T1-weighted (T1W) or fluid-attenuated inversion recovery (FLAIR) images at the sites of particular predilection, the parasagittal perirolandic cortex, and the depths of sulci (see Fig. 20.7). Decreased diffusion (increased signal) is seen on DWI (see Fig. 20.8). Selective cerebral cortical neuronal injury is usually accompanied by involvement of basal ganglia (especially dorsal putamen) and thalamus (especially lateral thalamus; see Fig. 20.9).

TABLE 20.16 Major Aspects of Magnetic Resonance Imaging in the Diagnosis of HIE in the Term Infanta Major conventional MRI findings in first week Cerebral cortical gray-white differentiation lost (on T1W or T2W) Cerebral cortical high signal (T1W and FLAIR), especially in parasagittal perirolandic cortex Basal ganglia/thalamus, high signal (T1W and FLAIR, usually associated with the cerebral cortical changes but possibly alone with increased signal in brain stem tegmentum in cases of acute severe insults; see Chapter 18) Parasagittal cerebral cortex, subcortical white matter, high signal (T1W and FLAIR) Periventricular white matter, decreased signal (T1W) or increased signal (T2W) Posterior limb of internal capsule, decreased signal (T1W or FLAIR) Cerebrum in a vascular distribution, decreased signal (T1W), but much better visualized as decreased diffusion (increased signal) on diffusion-weighted MRI Diffusion-weighted MRI more sensitive than conventional MRI, especially in first days after birth, when former shows decreased diffusion (increased signal) in injured areas a

See text for references and more details concerning timing of findings. FLAIR, Fluid-attenuated inversion recovery; MRI, magnetic resonance imaging; T1W and T2W, T1- and T2-weighted images.

In the unusual cases of principally deep nuclear and brain stem involvement, as with severe, acute asphyxial insults, high signal (T1W or FLAIR) is seen in the brain stem tegmentum as well as in the basal ganglia. DWI is more sensitive for detection of cerebral cortical and deep nuclear involvement (see Fig. 20.10). In one series of 173 encephalopathic term newborns, predominant involvement of perirolandic cortex and basal ganglia/thalamus was observed in 44 (25%) and in an additional 24 (14%) in association with predominant involvement of parasagittal regions.273 Parasagittal cerebral injury is seen readily as areas of increased signal (T1W and FLAIR) in the parasagittal cerebral cortex and subcortical white matter (see Figs. 20.11 and 20.12).

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Day 1

A

B

C

D

F

G

H

Day 10

E

Figure 20.6  Deep nuclear-cortical selective neuronal injury. An infant at 35 weeks of gestation with a history of placental abruption for several hours before hospital admission. Apgars 1 (at 1 minute), 3 (at 5 minutes), and 7 (at 10 minutes). No hypothermia therapy was commenced. Magnetic resonance imaging of axial imaging on the first day of life for diffusion-weighted imaging (A), apparent diffusion coefficient map imaging (B), T1-weighted imaging (C), and T2-weighted imaging (D) reveal isolated thalamic and deep nuclear gray-matter injury that is most apparent on the diffusion imaging (thick arrowheads). At day 10 there is now evolution, with more prominent T1- and T2-weighted signal changes in the deep nuclear gray matter and the thalamus, and prominent restriction in the cortical ribbon on diffusion-weighted (E) and apparent diffusion coefficient map (F, thick arrowheads) imaging, suggesting a secondary neuronal degeneration. The extent of the conventional injury in the deep gray matter is apparent (G and H). (Images were prepared by Dr Joshua Shimony, neuroradiologist at Washington University in St. Louis and are courtesy of ACOG.)

The relative distribution of the abnormalities among many large-scale MRI studies has varied somewhat because of different schemes for analysis (see Table 20.12).a In general, approximately 15% to 30% of MRI scans have been normal. Lesions in basal ganglia/thalamus, either predominantly or more commonly accompanying other areas of involvement, are present in approximately 40% to 80% of cases. Because the lesions in basal ganglia and thalamus often are microscopic in size, some instances of involvement likely may not be detected by MRI. Abnormalities of parasagittal (watershed) white matter and cortex are present in approximately 40% to 60%. The involvement of cortex in the watershed lesions also is likely an underestimate, because the cortical involvement typically is laminar (especially layers 3 and 5), and the entire cortical thickness in the human newborn is only approximately 2 mm.283 In more severe cases the classic watershed parasagittal cerebral injury involving cortex and subcortical/central white matter is readily apparent. Involvement of basal ganglia and brain stem preferentially occurs in approximately 10% to 20% of a

References 10, 28, 29, 229, 264, 270, 272, and 274-282.

cases, usually following a catastrophic sentinel event (see later). Preferential involvement of periventricular/central white matter, similar to periventricular leukomalacia of premature infants, is noted as a dominant feature in only approximately 15% of cases, and occurs especially in infants of somewhat lower gestational age (late preterms),279,280,284 or in the context of hypoglycemia or prolonged cardiovascular instability (e.g., congenital heart disease).285 Although many of the lesions just discussed are visualized well by conventional MRI, they are visualized better and, importantly, earlier by DWI (see Fig. 20.14). Increased signal on DWI, indicative of decreased water diffusion, has been shown in experimental models of focal cerebral ischemia and in adult stroke in the first 1 to 2 hours after the insult.286-292 Many studies of newborns with hypoxic-ischemic disease have demonstrated the superior sensitivity of DWI versus conventional MRI in delineating the site and extent of tissue injury early in the neonatal period.a The DWI signal in neonatal HIE is influenced greatly by the timing of the scan and the a

References 242, 243, 253, 254, 271, 279, and 293-301.

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Figure 20.7  Magnetic resonance imaging scan of cortical neuronal injury. The infant had severe apnea on the first day of life, and the scan was performed on the third postnatal day. On this parasagittal fluid-attenuated inversion recovery image, note the striking cortical highlighting, especially marked in the depths of sulci.

A

region studied.261,263-267,269,270 The timing of DWI abnormality in asphyxiated term infants with presumed selective neuronal necrosis or parasagittal cerebral injury, or both, is shown in Fig. 20.15.298 Thus, although some infants exhibit abnormality on the first day, injury is generally underestimated at that time. The nadir for diffusion occurs between the second and third days. By 7 to 8 days, pseudonormalization is apparent and is probably related to recovery processes that ultimately lead to angiogenesis and other factors causing increased diffusion. Thus, the optimal time for detection of DWI abnormality in the most common varieties of hypoxic-ischemic disease in the term newborn is approximately 2 to 3 days (see Fig. 20.15). In adult human stroke (i.e., permanent occlusion), diffusion is decreased in the first hours after the insult and remains low until pseudonormalization occurs at 7 to 9 days.302 This time course is similar to that observed in animal models of permanent vascular occlusion. By contrast, in newborns, the insult usually is transient and is followed by reperfusion. In animal models of transient occlusion, during the occlusion diffusion decreases, whereas on reperfusion, diffusion recovers before a secondary decline many hours later, as in the usual asphyxiated human infant (see Fig. 20.15). The evolution of these diffusion changes appears to be altered by the commencement of therapeutic hypothermia, which is associated with a more protracted pseudonormalization of the diffusion coefficient, with full normalization requiring greater than 10 days.303 This more protracted course may reflect a slower evolution to cell death and thereby provide a longer window for a second neuroprotective agent. Further studies are needed to confirm this evolution of the diffusion findings in the setting of therapeutic hypothermia.

B Figure 20.8  Magnetic resonance imaging (MRI) scans of selective neuronal injury. The infant experienced intrapartum asphyxia and had seizures on the first postnatal day. Scans were performed on the fifth postnatal day. (A) The axial fluid-attenuated inversion recovery image shows increased signal in putamen bilaterally (arrows) but no definite abnormality in the cerebral cortex. (B) By contrast, diffusion-weighted MRI (DWI) shows striking increased signal (i.e., decreased diffusion) in the frontal cortex (in addition to more pronounced basal ganglia abnormality).

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy

A

B

Figure 20.9  Magnetic resonance imaging scans of hypoxic-ischemic injury to basal ganglia and thalamus. Scans were obtained from a 5-day-old infant who experienced severe perinatal asphyxia. (A) Note in the parasagittal T1-weighted image markedly increased signal in the basal ganglia, especially the putamen (arrowheads), and in the thalamus (arrow). (B) The axial proton density image also demonstrates the injury well in the same distribution. (Courtesy Dr. Patrick Barnes.)

A

B

Figure 20.10  Diffusion-weighted magnetic resonance imaging (DWI) of deep nuclear and brain stem injury. This full-term infant experienced a severe late intrapartum asphyxial insult. MRI and DWI scans were carried out late on the first postnatal day. No definite abnormality was discerned by conventional MRI (not shown). However, DWI shows striking decreased diffusion (increased signal) in the basal ganglia–thalamus (arrows in A), the hippocampus (short arrows in B), and the midbrain tegmentum (long arrows in B).

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A Figure 20.12  Magnetic resonance imaging (MRI) scan of parasagittal cerebral injury. Coronal T1-weighted MRI, obtained on the fifth postnatal day in an asphyxiated term infant, shows striking, triangular lesions in the parasagittal areas bilaterally. The increased signal is also apparent in the basal ganglia and the thalamus bilaterally. (Courtesy Dr. Alan Hill.)

B Figure 20.11  Magnetic resonance imaging (MRI) scan of parasagittal cerebral injury. (A) Axial T2-weighted MRI scan obtained on postnatal day 5 from an infant with perinatal asphyxia and neonatal seizures shows a striking loss of normal cerebral gray–white matter signals symmetrically in parasagittal regions, especially posteriorly (arrows). A computed tomography (CT) scan obtained 2 days earlier (not shown) showed much less well-localized decreased attenuation. (B) Coronal T2-weighted MRI scan obtained on postnatal day 4 from an infant with perinatal asphyxia and neonatal seizures. Note the striking abnormality in parasagittal areas bilaterally (arrows). A CT scan performed 1 day before showed equivocal findings (not shown). (Courtesy Dr. Patrick Barnes.)

The importance of the region injured in the evolution of changes in diffusion is illustrated by the scans shown in Fig. 20.16.295 Thus, in this unusual example of precise knowledge of the timing of the insult (postnatal cardiac arrest), decreased diffusion in basal ganglia and thalamus was apparent at 6 hours of age, but decreased diffusion did not appear in the cerebral cortex until 32 hours. Other investigators showed that although severe white matter injury is associated with early decreased diffusion, with more moderate white matter injury

diffusion is normal or slightly increased early and increases in the ensuing days (Fig. 20.17).279 A similar increase in white matter diffusion was observed in cerebral hypoxia–ischemia in the neonatal rat.304 To summarize, MRI clearly provides superior imaging resolution for delineation of all hypoxic-ischemic lesions, both in the neonatal period and on follow-up (see Tables 20.15 and 20.16). DWI provides the capability for identification of injury by 24 to 48 hours after asphyxia in the term infant to assist in the early delineation of the nature and severity of cerebral injury.

Cerebral Metabolic-Hemodynamic Neurodiagnostic Studies Neurodiagnostic studies that address changes in metabolism and physiology after perinatal hypoxic-ischemic insults include MR spectroscopy, positron emission tomography (PET), near-infrared spectroscopy, and other measures of the cerebral circulation (see Chapter 10). Of these, MR spectroscopy has proven most useful for diagnostic assessment and is emphasized here.

Magnetic Resonance Spectroscopy MR spectroscopy has proven to be a diagnostic modality of particular importance in the evaluation of the infant with perinatal hypoxic-ischemic brain injury. Both phosphorus and proton MR spectroscopy are useful, although currently the more readily available proton MR spectroscopy is used most widely. Indeed, over the past few years at our institution, proton MR spectroscopy has joined DWI as part of the standard evaluation of infants evaluated by MR techniques for hypoxic-ischemic disease. The basic principles of phosphorus and proton MR spectroscopy and the normative data obtainable are described

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UP

B

A

Figure 20.13  Magnetic resonance imaging scan of multifocal ischemic brain necrosis. The scan was obtained at 6 weeks of age in an infant who had severe perinatal asphyxia. T1-weighted images in the (A) sagittal and (B) axial planes show striking changes consistent with multicystic encephalomalacia.

A

B

Figure 20.14  Common patterns of cerebral injury represented by diffusion-weighted images at days 2 to 3 after birth. The areas of injury appear bright. Panel A shows watershed injury, predominantly in the anterior and posterior watershed areas of the left hemisphere. Panel B shows the basal ganglia/thalamic injury.

in Chapter 10. The value of these techniques in the assessment of HIE in the term infant is summarized in Table 20.17.

Phosphorus Magnetic Resonance Spectroscopy.  Multiple

studies of infants who sustained perinatal asphyxia, especially intrapartum, have focused on phosphorus-31 (31P) spectra.305-314 The sequence of findings has been initially normal spectra (concentrations of phosphocreatine [PCr], inorganic phosphate [Pi],315 and adenosine triphosphate [ATP]) in the first hours after birth, followed by a decline in concentration of PCr and

a rise in that of Pi (and thus a decline in the PCr/Pi ratio) over approximately the next 24 to 72 hours (Fig. 20.18; see Table 20.17). In the most severely affected infants, ATP concentrations also decline at this time. Subsequently, spectra return to normal over the ensuing weeks, although the total 31P signal may be reduced when marked loss of brain tissue has occurred.308 This sequence of events is directly reminiscent of the progression of the “delayed energy failure” described in Chapter 13. This secondary energy failure correlates directly with the ultimate degree of cell death. Consistent with the experimental data, the severity of

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Unit IV  Hypoxic-Ischemic and Related Disorders Brief occlusion Sustained occlusion

ADC ratio 1.0

Time

A

ADC ratio 1.0

Phosphorus magnetic resonance spectroscopy Detects high-energy phosphates (PCr, ATP), inorganic phosphate, and pHi; in first few hours after insult PCr, ATP, and pHi are often normal. After approximately 8 h, with development of secondary energy failure, PCr (and later ATP) declines, and pHi increases. In first 1–2 weeks, the severity of decline in PCr and the increase in pHi correlate with the severity of brain injury. Proton magnetic resonance spectroscopy Detects multiple compounds, especially lactate, N-acetylaspartate, choline, creatine, and glutamate. Lactate is elevated as early as a few hours after the insult, and it appears to be an earlier indicator of brain injury than is diffusion-weighted magnetic resonance imaging. In the first days after insult, elevations of lactate (and perhaps glutamate) and declines in N-acetylaspartate are identified, and the severity of changes correlates with the severity of brain injury. a

0.6 Normothermic Hypothermic

B

TABLE 20.17 Value of Magnetic Resonance Spectroscopy in Assessment of HIE in the Term Infanta

0

2

4

8 6 Time (days)

10

12

Figure 20.15  (Panel A) The time course of apparent diffusion coefficient (ADC) change following brain injury. Blue represents a 30-minute occlusion. Black represents a 90-minute occlusion. The data are a composite from animal studies. (Panel B) The time course of ADC change following brain injury in term-born human infants. Red represents normothermic infants. Blue shows infants treated with therapeutic hypothermia. ADC ratios rather than absolute ADC values are used in the ordinate of both panels because ADC values vary regionally in infants and the areas of injury vary infant to infant. The ratio represents injured tissue over normal tissue, so values < 1 indicate a reduction in ADC values. (A, adapted from McKinstry RC, Miller JH, Snyder AZ, et al. A prospective, longitudinal diffusion tensor imaging study of brain injury in newborns. Neurology. 2002;59(6):824–833; and B, adapted from Bednarek N, Mathur A, Inder T, et al. Impact of therapeutic hypothermia on MRI diffusion changes in neonatal encephalopathy. Neurology. 2012;78:1420–1427.)

this delayed energy failure in human infants correlates closely with the severity of the neonatal neurological syndrome (Fig. 20.19) and with the subsequent occurrence of neurological deficits (see later).311,312,314 The findings not only demonstrate the value of phosphorus MR spectroscopy in the early delineation of impairments of energy metabolism in the asphyxiated infant but also provide important prognostic information (see the section on prognosis). Phosphorus MR spectroscopy also is valuable in detection of a paradoxical postischemic increase in intracellular pH (pHi).314 The evolution of this increase in the days to weeks after hypoxia-ischemia correlates with the degree of brain injury. This postischemic alkalinization may lead to cellular injury and appears related, in considerable part, to postischemic activation of the neuronal and glial sodium-hydrogen transporter. Consistent with

See text for references. ATP, Adenosine triphosphate; HIE, hypoxic-ischemic encephalopathy; PCr, phosphocreatine; pHi, intracellular pH.

this formulation, experimental data indicate a neuroprotective role for amiloride, a sodium-hydrogen exchange blocker, when administered after ischemia (see Chapter 13 and later).

Proton Magnetic Resonance Spectroscopy.  Proton MR spectroscopy (see Chapter 10) has been applied extensively to the study of infants with HIE.272,295,313,316-344 Although not all the reported observations are entirely consistent, important and consistent findings can be recognized (see Table 20.17). First, in the acute period, as early as a few hours after birth, elevation in cerebral lactate, often expressed as the ratio of lactate to N-acetylaspartate (NAA), creatine, or choline, can be detected (see Fig. 20.10A). Indeed, detection of lactate by proton MR spectroscopy is a more consistent indicator of brain injury than is DWI (or other imaging modality) in the first hours after hypoxic-ischemic injury.330 Currently, MR spectroscopy may be considered as the most sensitive modality for detection of neonatal brain disturbance in the acute period. More data regarding sensitivity and specificity for structural injury are needed. During this early period, ratios of NAA to choline or creatine have been either unchanged or only slightly decreased. The elevated lactate is most pronounced in deep nuclear structures, especially basal ganglia and thalamus, with their high metabolic rate and propensity for hypoxic-ischemic injury. The acutely elevated lactate correlates with the severity of the neonatal neurological syndrome, the subsequent delayed energy failure (Fig. 20.20B), and the neurological deficits on follow-up (see the section on prognosis). Lactate levels may remain elevated for weeks, perhaps in part because of enhanced glycolysis and lactate production by astrocytes. Second, after days to weeks, ratios of NAA to choline or creatine decline and reflect tissue injury. Recall from Chapter 10 that NAA is contained in neurons (and presumably axons) and in

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy

A

B

C

D

531

Figure 20.16  Differential regional decreases in diffusion after neonatal hypoxia-ischemia. Diffusion-weighted magnetic resonance imaging (DWI) images A and B, obtained 6 hours after cardiorespiratory arrest, show a bright signal (i.e., decreased diffusion) in the basal ganglia (thick arrows), the thalami (curved arrows), and the dorsal brain stem (thin arrows). There is no decrease in diffusion in the cerebral cortex. DWI images C and D, obtained 32 hours after cardiorespiratory arrest, show persistence of the decreased diffusion in deep nuclear structures and a bright signal (decreased diffusion) in the cerebral cortex. Conventional magnetic resonance imaging (not shown) at 6 hours was normal, but at 32 hours it was clearly abnormal. (From Soul JS, Robertson RL, Tzika AA, du Plessis AJ, et al.Time course of changes in diffusion-weighted magnetic resonance imaging in a case of neonatal encephalopathy with defined onset and duration of hypoxic-ischemic insult. Pediatrics. 2001;108:1211–1214.)

oligodendroglial precursors. Thus, the declines in NAA in both gray and white matter are not surprising. The severity of the decline in NAA correlates with the severity of subsequent neurological deficits. Glutamate levels also have been shown to be elevated in the first days of life in infants with severe HIE.329 This determination is more difficult than that for lactate or NAA and may not be as useful.

Positron Emission Tomography Although PET is not a routine diagnostic procedure (for the reasons described in Chapter 10), the technique has provided major insight into the frequency, basic nature, and probable pathogenesis of the cerebral injury observed in asphyxiated term infants.345 Because experience with adult patients had indicated that measurements of regional cerebral blood flow

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ADC ×10–3/mm2/s

2.0

55 h

1.5 36 h 1.0 31 h

1 23 4 5

0.5 0

5

10

Figure 20.17  Diffusion abnormalities in cerebral white matter after apparent neonatal hypoxia-ischemia. The infants were born at term and were control (+), with severe white abnormalities on conventional magnetic resonance imaging (MRI) (●), or with moderate white matter abnormalities (△) on conventional MRI. Note in the infants with severe white matter abnormalities, diffusion was clearly decreased in the first week, whereas in the infants with moderate abnormalities, diffusion was not decreased. A nonsignificant increase in diffusion was noted in the latter infants after the first week. (Based on Rutherford M, Counsell S, Allsop J, et al. Diffusion-weighted magnetic resonance imaging in term perinatal brain injury: a comparison with site of lesion and time from birth. Pediatrics. 2004;114:1004–1014.)

7

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146 h

74 h 50 h 26 h

(CBF) provided critical information concerning the topography of hypoxic-ischemic cerebral injury, PET was studied in a series of 17 asphyxiated term infants with the H215O technique to measure regional CBF.345 The infants had experienced primarily intrapartum asphyxia, exhibited the clinical syndrome described earlier, including proximal limb weakness, and were evaluated by PET during the acute period of their illness (i.e., the first week). The disturbance of regional CBF in the asphyxiated infants constituted a continuum of deviation from the normal (or nearly normal) pattern. The consistent and apparently unifying abnormality was a relative decrease in CBF to parasagittal regions, generally symmetrical and more marked posteriorly than anteriorly. The extent of the relative decreases in parasagittal CBF correlated directly with the severity of clinical manifestations.345 The structural correlates of the decrease in CBF in parasagittal regions were elucidated in four infants by technetium brain scan and by neuropathology and consisted of parasagittal cerebral injury. Thus, our CBF findings by PET indicated that parasagittal cerebral injury is a common feature in neonatal HIE, at least in patients who survive the perinatal insult.345 This observation has been confirmed and amplified by subsequent studies with MRI (see earlier discussion).

CLINICOPATHOLOGICAL CORRELATIONS The neurological correlates of HIE, as observed in the neonatal period and subsequently, are understood when one recalls the topography of the neuropathological lesions. Considerably more is known about the long-term neurological correlates of the several lesions than about the correlates in the newborn period. Indeed, in the latter instance, correlates must be made with some reservation. The reasons for the difficulty in establishing

4h 15 10 5 0 –5 –10 –15 –20 –25 ppm

Figure 20.18  Phosphorus (P)-31 magnetic resonance spectra from two asphyxiated infants born at 37 and 36 weeks of gestation. Postnatal ages at the time of study are indicated. (Top) Peak assignments (numbers 1 to 7) are as follows: 1, phosphomonoester (PME); 2, inorganic P (Pi); 3, phosphodiester (PDE); 4, phosphocreatine (PCr); 5, 6, and 7, gamma, alpha, and beta nucleotide triphosphate (mainly adenosine triphosphate [ATP]). At 8 hours, spectra were within normal limits (i.e., PCr/Pi was 0.99, ATP/total P was .09, and intracellular pH [pHi] was 7.06; pHi rose to a maximum of 7.28 at 36 hours). Minimum value for PCr/Pi was 0.32 at 55 hours, when ATP/total P was only .04 and pHi was 6.99. The infant died at age 60 hours. (Bottom) At 4 hours, PCr/Pi and ATP/total P were normal at .97 and .09, respectively, and pHi was 7.08 (pHi rose to a maximum of 7.23 at 26 hours). The minimum value for PCr/Pi was 0.65 at 50 hours, but by 146 hours it was normal. ATP/total P never fell below normal. However, the infant died at age 27 days with cerebral atrophy. (From Azzopardi D, Wyatt JS, Cady EB, et al. Prognosis of newborn infants with hypoxic–ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res. 1989;25:445–451.)

correlations relate primarily to the large degree of overlap in the occurrence of the basic lesions and to the heretofore imperfect definition of topography by available imaging studies. Although the overlap of the various lesions will be a persistent confounder, improvements in imaging, especially the use of MRI, have allowed better definition of the topography of the brain injury in the neonatal period. The latter now has allowed certain probable correlations to be made. In the following discussion, we review the major neuropathological lesions in terms of the neurological correlates in the newborn period and subsequent periods (i.e., neurological sequelae).

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy PCr/Pi

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Figure 20.19  Relationship between cerebral levels of high-energy metabolites (mean ± SD), determined by phosphorus magnetic resonance spectroscopy, and the severity of the neonatal neurological syndrome (NNS) in 23 asphyxiated term newborns. The numerical scoring was as follows: NNS1, severe; NNS2, moderate; NNS3, mild; and NNS4, normal neurological examination in healthy control infants. ATP, adenosine triphosphate; PCr, phosphocreatine; Pi, inorganic phosphate. (From Martin E, Buchli R, Ritter S, et al. Diagnostic and prognostic value of cerebral 31P magnetic resonance spectroscopy in neonates with perinatal asphyxia. Pediatr Res. 1996;40: 749–758.)

TABLE 20.18  Clinical Correlates of Selective Neuronal Necrosisa NEUROLOGICAL FEATURESb

TOPOGRAPHY OF THE MAJOR INJURY

NEONATAL PERIOD

LONG-TERM SEQUELAE

Cerebral cortex; basal ganglia; thalamus; reticular formation; brain stem nuclei, including inferior colliculus, cochlear nuclei, and motor nuclei of cranial nerves; cerebellum; anterior horn cells

Stupor and coma Seizures Hypotonia Hypertonia-dystoniac Oculomotor disturbancesd Disturbed sucking, swallowing, and tongue movementsd

Cognitive deficitsc Spastic quadriparesis Choreoathetosisc Dystoniac Seizure disorder Ataxia Bulbar and pseudobulbar palsyd

a

As discussed in the text, three major forms of selective neuronal necrosis should be recognized: diffuse, cerebral cortical–deep nuclear, and deep nuclear–brain stem. All the neurological features may be seen to varying degrees in the diffuse form of selective neuronal necrosis. c Common abnormalities in those infants with involvement of basal ganglia and thalamus. d Common additional abnormalities in those infants with involvement of brain stem tegmentum (and usually associated with deep nuclear involvement). b

Selective Neuronal Necrosis Neonatal Correlates The neurological correlates in the neonatal period are diverse, as is the topography of the major neuronal injury (Table 20.18). Of the major varieties of selective neuronal necrosis (diffuse, cerebral cortical–deep nuclear, deep nuclear–brain stem, and pontosubicular necrosis [see Chapter 18]), tentative clinical correlates can be established for the first three. In the diffuse variety of selective neuronal necrosis, associated with very severe and prolonged insults, all levels of the neuraxis are affected. With this variety, we have attributed the derangement of the level of consciousness to the involvement of the bilateral cerebral hemispheres or the reticular activating system in the upper brain stem and diencephalon, including the thalamus. Indeed, in one careful series studied by MRI, the involvement of basal ganglia and thalamus was associated strongly with severe encephalopathy, including a decreased level of alertness.278 Seizures appear to relate to cerebral cortical injury, although some of the seizure phenomena, especially some of the tonic

phenomena, may emanate from subcortical nuclear structures in basal ganglia, thalamus, or midbrain. The uncommon but dramatic occurrence of the syndrome of inappropriate ADH secretion or diabetes insipidus presumably relates to hypothalamic neuronal involvement. The hypotonia could relate to cerebral cortical or anterior horn cell disturbances or combinations of both. Electrophysiological evidence (e.g., fibrillations), as well as clinical data (hypotonia, absent deep tendon reflexes, weakness), support a role for anterior horn cell involvement, especially in severe, diffuse disease.346,347 The oculomotor abnormalities presumably relate primarily to the disturbance of cranial nerve nuclei (III, IV, and VI). The impairments of sucking (V), swallowing (IX and X), and tongue movements (XII) also are probably largely the basis of brain stem cranial nerve nuclear involvement. However, a contribution of corticobulbar disturbance to these deficits is possible. The facial appearance of an infant with striking brain stem involvement, proven neuropathologically, is shown in Fig. 20.21.

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Unit IV  Hypoxic-Ischemic and Related Disorders NAA Cho

Cr

Glx

Lac

4

A

3

2 ppm

1

0

Figure 20.21  Facial appearance at age 1 month in an infant who experienced perinatal asphyxia. Note the disconjugate gaze, ptosis, marked facial weakness, and wide-open mouth. The infant also exhibited fasciculations of the tongue on physical examination. (From Roland EH, Hill A, Norman MG, et al. Selective brainstem injury in an asphyxiated newborn. Ann Neurol. 1988;23:89–92.)

5

Lac/Cr

4 3 2 1 0

B

0.0

0.5

1.0 PCr/Pi

1.5

2.0

Figure 20.20  Proton magnetic resonance (MR) spectroscopy from basal ganglia in 16 asphyxiated term newborns. (A) Spectra from a control infant (upper tracing) and from a severely asphyxiated infant (lower tracing), both obtained at 14 hours of age. Note the striking lactate peak in the asphyxiated infant. (B) Relationship between lactate/creatine (Lac/Cr) measured by proton MR spectroscopy at 4 to 18 hours of age and phosphocreatine/inorganic phosphate (PCr/Pi) measured by phosphorus MR spectroscopy at 33 to 106 hours. Note the correlation between the severity of the early increase in lactate and the degree of secondary energy failure as manifested by the decreased PCr/Pi ratio. Cho, choline; Glx, glutamic acid; NAA, N-acetylaspartate. (From Hanrahan JD, Sargentoni J, Azzopardi D, et al. Cerebral metabolism within 18 hours of birth asphyxia: a proton magnetic resonance spectroscopy study. Pediatr Res. 1996;39:584–590.)

With the cerebral cortical–deep nuclear variety of selective neuronal necrosis, associated with moderate to severe and relatively prolonged insults, the involvement of the cerebral cortex, the basal ganglia (especially the putamen), and the thalamus predominates (see Chapter 18). The major clinical difference from the syndrome just described is the occurrence of increased tone in many such affected infants. The hypertonia often increases with stimulation, especially manipulation, and has characteristics of dystonia. We have attributed this finding to extrapyramidal involvement, perhaps unmasked by the less severe injury to the pyramidal system that occurs with the diffuse variety of selective neuronal injury. With the deep nuclear–brain stem variety of selective neuronal necrosis, associated with severe and abrupt insults, the involvement of the basal ganglia, thalamus, and brain stem tegmental neurons occurs, with relative sparing of the cerebral cortex. The major additional clinical correlates relate to brain stem injury and include ptosis, oculomotor disturbances, facial diparesis, ventilatory disturbances, and impaired sucking and swallowing.61,348,349

Long-Term Correlates The long-term neurological sequelae depend on the topography of the neuronal injury. With the diffuse variety of selective neuronal necrosis, intellectual retardation is nearly uniform and is the consequence principally of cerebral cortical injury (see Table 20.18). However, injury to the basal ganglia,350,351 thalamus, and cerebellum (see later) could play a role. (The possibility of impairment of subsequent cortical neuronal differentiation is raised by experimental data,352,353 but studies of human infants

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy are lacking.) The spastic motor deficits could relate to cortical injury, although the relative roles of concomitant ischemic parasagittal cerebral injury and cerebral white matter injury/ periventricular leukomalacia have not been elucidated. Seizure disorders, which develop in approximately 10% to 30% of infants with HIE (see Chapter 12), probably relate to cerebral cortical injury. Impairment of cortical visual functions occurs in severely affected infants, and cerebral cortical atrophy was reported to be the principal finding on CT in approximately 60% of such patients.354-357 MRI studies have emphasized the association of basal ganglia or thalamic lesions and cerebral white matter injury with impaired visual function in such infants.358-360 (The improvement of vision in as many as 50% of such infants over the first 2 years of life may reflect the operation of cortical organizational events, i.e., brain plasticity, as outlined in Unit I.) Disturbances of hypothalamic neurons presumably underlie the early sexual maturation that occurs in 10% of term asphyxiated infants with other signs of neurological disturbance.361 Impairments of sucking, swallowing, and facial movement may relate to nuclear injury (i.e., bulbar palsy), although some infants also exhibit the features of upper motor neuron injury (i.e., pseudobulbar palsy), probably cerebral in origin, such as “all-or-none smile” and fixed facial expression with drooling.362,363 Hyperactivity and impaired attentive capacities, particularly observable (unmasked?) in less affected patients, may relate to involvement of neurons of the reticular activating system, the basal ganglia, or the cerebellum.364-366 The substantial minority of infants with hearing deficits presumably may have involvement of dorsal cochlear nuclei (which subserve perception of higher frequency sounds) or of cochlea, or both. The involvement of the superior olivary nucleus and the inferior colliculus may contribute. Finally, the involvement of anterior horn cells may explain the characteristic persistence of hypotonia in the first months of life, and when it is severe, this topography of involvement may explain the unusual persistence into childhood of hypotonia and weakness (i.e., atonic quadriparesis or “atonic cerebral palsy”). With the cerebral cortical–deep nuclear variety of selective neuronal necrosis, the major clinical features include not only the deficits attributable to cerebral cortical neuronal injury but also those related to the involvement of the basal ganglia and the thalamus, which are discussed separately later. With the deep nuclear–brain stem variety of selective neuronal necrosis, the additional clinical features relate not only to the basal ganglia–thalamic involvement, discussed separately later, but also to the brain stem injury. All surviving infants with this injury have prolonged difficulties with feeding, usually for many months and often requiring tube feeding.61,348,367,368 Approximately 20% to 30% require gastrostomy for feeding (see the later section on prognosis). However, because of the relative sparing of cerebral cortex with this variety of selective neuronal injury, up to 50% of these patients have been found to exhibit normal cognition.61 With involvement of basal ganglia and thalamus, whether as a component of the cerebral–deep nuclear variety of selective neuronal necrosis or the deep nuclear syndrome with brain stem involvement, subsequent extrapyramidal abnormalities are not uncommon. The neurodevelopmental, motor, and feeding outcomes of a large series of infants with basal ganglia and thalamic injury on MRI have been recently reviewed (see Prognosis).275,276,369 Unknown numbers of such infants develop

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the neuropathological lesion status marmoratus (see Chapter 18), but the fundamental clinicoanatomical correlate is neuronal loss in the putamen and the thalamus, whether or not the final pathological appearance is that of status marmoratus.370,371 The essential anatomical combination for choreoathetosis and dystonia appears to be bilateral involvement of the basal ganglia and intact pyramidal tracts because, in one neuropathological series, the several patients without choreoathetosis had unilateral or bilateral sparing of the basal ganglia or degeneration of the pyramidal tracts.372 The thalamoputaminal involvement is different from the subthalamic nucleus and globus pallidus distribution in bilirubin encephalopathy, the other major neonatal disorder with subsequent choreoathetosis (see Chapter 26). Careful studies using MRI in infants with “dyskinetic” or “athetoid” cerebral palsy demonstrated the thalamoputaminal predilection in hypoxic-ischemic disease.373,374 Indeed, the thalamus was affected without putaminal involvement as often as with putaminal involvement, and more often than with the involvement of the putamen alone.373 Of particular interest and not readily explicable is the finding that the onset of the extrapyramidal abnormalities is not clearly apparent until after 6 to 12 months and often much later. Thus, most such infants develop overt choreoathetosis or dystonia, or both, between 1 and 4 years of age.375-377 Abnormal motor development and hypertonia commonly are obvious before this time (i.e., as early as 6 months of life).360 An important percentage of children will not develop abnormal movements until as late as 7 to 14 years of age (see Table 20.19).377-381 In the largest reported series of the delayed-onset syndrome, the mean age of onset of choreoathetosis and dystonia was 12.9 years, and the mean duration of progression was 7 years (Table 20.19).381 Four of the 10 patients studied had attained early developmental milestones at ages within the normal range. Although the children ultimately had mild to moderate motor disability, all were ambulatory. The only class of drugs with clear benefit was anticholinergic medication, perhaps reflecting that the relatively spared cholinergic neurons were responsible for the development of the extrapyramidal clinical phenomena.381 Intellectual function often is relatively preserved in those infants with choreoathetosis. Thus, in the older literature, intellectual function in infants with “athetoid cerebral palsy,” presumably many or most of whom had putaminothalamic

TABLE 20.19 Delayed-Onset Dystonia After Perinatal Asphyxia The mean age of onset of dystonia, often with choreoathetosis, is 12.9 years. Nearly 50% of patients have a history of normal neurological development. Approximately 80% have other neurological signs, but fewer than 50% have overt “cerebral palsy.” Intellect is in normal range in approximately 80%. Progression of dystonia continues for a mean of 7 years to moderate disability (not wheelchair bound). Treatment with anticholinergic agents may be beneficial. Data from Saint-Hilaire MH, Burke RE, Bressman SB, et al. Delayed-onset dystonia due to perinatal or early childhood asphyxia. Neurology. 1991;41:216–222.

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injury to a varying degree, was not noted to be markedly affected consistently.382-385 In the largest reported series of the delayed-onset extrapyramidal syndrome, 8 of 10 individuals had a normal intelligence quotient.381 The pathological substrate for the intellectual failure with injury to the basal ganglia and the thalamus presumably relates, in considerable part, to any associated hypoxic-ischemic cerebral cortical neuronal injury; indeed, in the large neuropathological series of Malamud,372 approximately 50% of patients with severe involvement (i.e., the pathological features of status marmoratus) exhibited neuropathological signs of cerebral cortical injury. However, these latter patients also manifested thalamic injury, and approximately one-third of patients with pathologically proven status marmoratus, and with impaired intellect, exhibited thalamic injury without significant involvement of the cerebral cortex.372 This finding suggests that the thalamic injury can play an important role in causing the intellectual deficits. MRI data support this contention (see the section on prognosis).29,386 These observations have major implications for the role of the thalamus in the development of intellectual function. The clinical correlates of the cerebellar vermian atrophy/ hypoplasia that is a common sequela in term infants with hypoxic-ischemic disease (see Chapter 18) remain to be defined. This abnormality may contribute to varying degrees of motor incoordination, occasionally including overt ataxia. Cognitive and behavioral deficits also could be correlates of the cerebellar involvement (see later).

Parasagittal Cerebral Injury Neonatal Correlates The neurological correlates in the neonatal period include particularly weakness of proximal limbs, which is consistently more prominent in the upper rather than the lower extremities (Table 20.20). This pattern of weakness is readily predicted from the topography of the lesion (Fig. 20.22). The topographical

TABLE 20.20 Clinical Correlates of Parasagittal Cerebral Injury

TOPOGRAPHY OF THE MAJOR INJURY Cerebral cortex and subcortical white matter, superomedial (parasagittal) convexities, and posterior > anterior cerebrum

NEUROLOGICAL FEATURES NEONATAL PERIOD

LONG-TERM SEQUELAE

Proximal limb weakness upper > lower

Spastic quadriparesis Intellectual deficits (often “specific”)

Parasagittal cerebral injury distribution

Figure 20.22  Schematic diagram of representation of the homunculus on the motor cortex and the sites of parasagittal cerebral injury (red triangular areas bilaterally). Note that the proximal extremities, upper more than lower, are most likely to be affected.

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy

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representation of the homunculus on the motor cortex indicates that the proximal extremities, upper more than lower, lie within the distribution of the necrosis of the cerebral cortical neurons and their descending corticospinal tract fibers in subcortical white matter. Other deficits referable to parasagittal cerebral injury are likely, but ready detection of such deficits in the newborn requires specialized clinical techniques. For example, careful analysis of “cortical” somesthetic-visual-auditory associations, functions residing within the areas of posterior cerebrum especially affected in parasagittal necrosis, has not been accomplished in the newborn. This topic is clearly important for future clinical research. The advances in electrophysiological, behavioral, and functional MR techniques for assessing such associative functions in the newborn (see Chapters 9 and 10) could be used effectively in this clinical setting. Indeed, the disturbances of visual- and somatosensory-evoked responses observed in asphyxiated infants appear to correlate with cerebral injury in the parasagittal cerebral distributions, affecting parieto-occipital regions in the former instance (visual-evoked responses) and parietal regions in the latter instance.354,387

indicated by more recent data. In the following discussion, the relative value of each of these factors in estimating outcome is evaluated. An important general question to consider is the spectrum of neurological deficits observed subsequently, and specifically, whether impairment of cognitive functions can occur in the absence of prominent motor deficits (i.e., cerebral palsy). Large-scale studies show that cognitive impairment without overt cerebral palsy is not uncommon after neonatal HIE.386,388,394-396 In the largest available series, among survivors of HIE, 9% of children without cerebral palsy had an IQ at 6 to 7 years of less than 70 and fully 31% had scores ranging from 70 to 84.396 Children with cerebral palsy did have a poorer cognitive outcome (i.e., 96% had an IQ < 70). Overall, 14% of infants treated with hypothermia developed cerebral palsy, versus 28% of those not treated with hypothermia, and the rates of occurrence of cognitive impairment without cerebral palsy were approximately similar in the two treatment groups.

Long-Term Correlates

Because hypoxic-ischemic injury is one cause of depressed Apgar scores, and because depressed Apgar scores imply the possibility of an ongoing hypoxic-ischemic insult, correlation of outcome with such scores has been attempted for many years. This approach is fraught with hazards for several reasons. First, precise quantitation of the Apgar score varies among observers, sometimes considerably. Second, each of the five factors that make up the score is given equal weight, and clearly the importance of each for central nervous system integrity differs greatly. Third, causes of the depressed scores, other than hypoxic-ischemic insult,397-404 include laryngeal inhibition (e.g., caused by aspiration of a small amount of amniotic fluid or by oronasopharyngeal–laryngeal stimulation from suction catheters), maternal medications or anesthesia, and prematurity, and are associated with generally favorable prognoses unless additional postnatal insults occur. In a population-based cohort study of 235,165 term infants, of the 292 with a 5-minute Apgar score of 0 to 3, only 16, or 6.8%, later exhibited cerebral palsy.405 Similarly, in another series of 1200 consecutive deliveries, only 20% of infants with a 5-minute Apgar score of less than 7 had acidosis with a pH of 7.10 or less (umbilical artery).406 This tenuous relationship between apparent fetal asphyxia and low Apgar scores has been confirmed.53,400,407-412 The value of the “extended” Apgar score (i.e., the score after 5 minutes) was demonstrated initially by data from the Collaborative Perinatal Project of the National Institutes of Health and was published over 35 years ago (Table 20.21).413 The likelihood of cerebral palsy in infants weighing 2500 g or more increased dramatically with the increasing duration of Apgar scores of 3 or less, especially after 15 minutes. Infants with such scores experienced a progressive increase in mortality rate, so that almost 60% of those with Apgar scores of 0 to 3 after 20 minutes subsequently died. Similarly, premature infants also exhibited a distinctly worsening prognosis with low “extended” Apgar scores. It is likely that the major determinant of the poor outcome with longer duration of a low Apgar score in both premature and full-term infants was, in the largest part, the severity of the initial intrauterine insult. However, even though low Apgar scores for as long as 15 minutes are associated with high mortality rates, the majority of survivors escaped major

The long-term sequelae of parasagittal cerebral injury relate primarily to motor and cognitive function, particularly the latter.29,274,281,388,389 However, in general, subsequent deficits are less common than in infants who also exhibit deep nuclear injury (see the section on prognosis later).29 The motor deficits, when present, include particular involvement of proximal limbs, upper more than lower, as in the neonatal period (see Table 20.20). Although severely affected infants exhibit multiple cognitive deficits, many infants have exhibited “specific” intellectual deficits, such as disproportionate disturbances in the development of language or of visual-spatial abilities, or both.388,390-393 We believe these discrete intellectual deficits to relate particularly to the larger, posteriorly located lesions (i.e., in posterior parietal-occipital-temporal regions) that reside within areas of critical importance for many associative functions, especially those relating to auditory and visual input and output, and to a variety of visual–motor phenomena.

PROGNOSIS Precise determination of the prognosis in the term newborn who sustains a hypoxic-ischemic insult is hindered by the difficulties in determining the severity of the insult. As indicated earlier, most of the primary insults occur in utero, and the difficulties of determining the degree of hypoxemia and ischemia in the fetus are obvious. The value of electronic fetal monitoring and associated fetal blood sampling may be appreciable, but further advances in monitoring the status of the fetal brain clearly are needed (see Chapter 17). Because significant intrauterine (particularly intrapartum) hypoxic-ischemic insult is usually associated with depressed Apgar scores, correlation of outcome with the Apgar score also has been used for assessing the prognosis. The presence of a neonatal neurological syndrome is a crucial indicator of a perinatal insult with the potential to cause neurological injury. Moreover, certain specific aspects of the neurological syndrome (e.g., seizures and duration of abnormalities) are useful in estimating outcome. Finally, selected neurodiagnostic studies, such as EEG, evoked potentials, ultrasound, CT, and MRI, are also of proven prognostic value. Value for MR spectroscopy is also

Apgar Scores, Fetal Acidosis, and Neonatal Resuscitation

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TABLE 20.21 Relation of Apgar Score to Mortality and Cerebral Palsya APGAR SCORE OF 0–3 1 min 5 min 10 min 15 min 20 min

DEATH IN FIRST YEAR (%)

CEREBRAL PALSY IN SURVIVORS (WITH KNOWN OUTCOME) (%)b

3 8 18 48 59

1 1 5 9 57

For infants ≥2501 g. Neurological sequelae less pronounced than cerebral palsy were not quantitated. Adapted from Nelson KB, Ellenberg JH. Apgar scores as predictors of chronic neurologic disability. Pediatrics. 1981;68:36–44. a

b

neurological injury (see Table 20.21). It is important to note that neurological sequelae less severe than cerebral palsy were not quantitated in this earlier study.53,404,414-416 Even with the worst of Apgar scores at 1 minute of age (i.e., 0 or apparent stillbirth), in a large series (n = 93), of the 40% of infants who survived, approximately 60% had a normal outcome.416 However, of the 58 infants whose Apgar score still was 0 at 10 minutes of age, 57 died, and the sole survivor had an abnormal neurological outcome. More recent data in the era of hypothermia treatment suggest value for the 10-minute Apgar score. Thus, in a substudy of 174 infants in the NICHD randomized, controlled trial of therapeutic hypothermia, 64/85 (75%) of those with a 10-minute Apgar score of 0 to 3 had death/disability compared with 40/89 (45%) of those with scores greater than 3. Each point increase in the 10-minute Apgar scores was associated with a significantly lower adjusted risk of death/disability, death, death/IQ < 70, death/cerebral palsy (CP), and disability/IQ < 70 and CP among survivors (all P < 0.05). Among the 24 children with a 10-minute Apgar score of 0, five (21%) survived without disability. The risk-adjusted probabilities of death/disability were significantly lower in cooled infants with Apgar scores of 0 to 3. The authors concluded that although the low 10-minute Apgar scores were associated with poorer school-age outcomes, approximately 20% of infants with a 10-minute Apgar score of 0 survived without disability to school age.417 Finally, a novel method of adapting the original Apgar score to provide a combined score418 that includes elements of respiratory management, chest compressions and the administration of drugs, in addition to the elements of the traditional Apgar score, has been shown to improve the short-term predictive power of this resuscitative evaluation (Table 20.22). Future data may show that this combined score better correlates with outcomes. The severity of fetal acidosis, as determined by the measurement of umbilical arterial pH and base deficit, is a useful reflection of the severity and duration of intrauterine hypoxia–ischemia. The relationship between the severity of fetal acidosis and neonatal neurological features as well as neurological outcome is reviewed in Chapter 17.

TABLE 20.22 New Expanded and Traditional Apgar Score for Evaluation of the Newborn Infant Expanded Apgar C Continuous positive airway pressurea O Oxygen M-B Mask and bag ventilationb I Intubation and ventilation N Neonatal chest compression E Exogenous surfactant D Drugs Scoring each item of expanded Apgar: 0 = intervention was performed; 1 = no intervention was performed a : score 0 if “mask and bag” or “intubation and ventilation” is scored 0 b : score 0 if “intubation and ventilation” is scored 0 Traditional Apgar A Appearance (skin color) 2 = completely pink 1 = centrally pink with acrocyanosis 0 = centrally blue or pale P Pulse (HR) 2 = > 100 beats per minute 1 = < 100 beats per minute 0 = no heart beat G Grimacing (reflex) 2 = Appropriate for gestational age 1 = Reduced for gestational age 0 = No reflex response A Activity (muscle tone) 2 = Appropriate for gestational age 1 = Reduced for gestational age 0 = No reflex response R Respiration (chest movement) 2 = Regular chest movement 1 = Small or irregular chest movement 0 = No chest movement HR, Heart rate.

Certain aspects of the neonatal resuscitation, and particularly the need for positive pressure ventilation and more intensive cardiopulmonary resuscitation efforts (e.g., chest compressions), are predictive of an unfavorable outcome. Hence, as outlined earlier the Combined Apgar score uses this information in addition to the parameters of the traditional Apgar score for prognostication (see Table 20.22). In one careful study, when the need for cardiopulmonary resuscitation was associated with evidence of fetal acidemia (pH < 7.00), five of five infants either died in the neonatal period or exhibited neonatal seizures, whereas of 10 infants requiring such resuscitation measures, but without evidence of an appreciable intrauterine insult (cord pH normal), all 10 had a normal outcome.419 In a later study, the requirement for intubation in full-term infants with severe fetal acidemia (i.e., umbilical arterial pH ≤ 7.0) was associated with a 6.4-fold increase in abnormal neurological outcome.82 The importance of the duration of delayed onset of breathing, also presumably reflecting the severity of the intrauterine insult, was emphasized by a study of 165 infants who exhibited “postasphyxial encephalopathy.”420 Thus, the

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy

TABLE 20.23 Relation of Three Key Early Neonatal Variables to Risk of Severe Adverse Outcome With Neonatal HypoxicIschemic Encephalopathy PROBABILITY OF SEVERE OUTCOMEa VARIABLES None One variable CC Resp. BD Overall Two variables CC and Resp. CC and BD BD and Resp. Overall Three variables CC and Resp. and BD

PERCENTAGE OF TOTAL

95% CONFIDENCE INTERVAL

46

33–58

69 67 6 64

NA NA NA 54–73

67 77 81 77

NA NA NA 66–85

93

81–99

a

Severe adverse outcome was defined as death or severe neurological disability; total N = 302. BD, Base deficit ≥16; CC, chest compression for >1 minute; NA, not applicable; Resp., age at onset of respiration ≥30 minutes. Data from Shah PS, Beyene J, To T, et al. Postasphyxial hypoxic–ischemic encephalopathy in neonates: outcome prediction rule within 4 hours of birth. Arch Pediatr Adolesc Med. 2006;160:729–736.

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1970s, but before the era of hypothermia treatment, support this contention and suggest the occurrence of improvements in overall outcome.a In an excellent representative earlier series of 93 patients (most term infants) reported by Brown and co-workers11 in 1974, perinatal asphyxia was manifested by such features as meconium-stained amniotic fluid, fetal bradycardia, the need for endotracheal intubation, assisted ventilation at birth, and Apgar scores of less than 3 at 1 minute, or less than 5 at 5 minutes, in addition to neurological signs, such as feeding difficulties, apnea, seizures, and hypotonia. Approximately 20% of the infants died in the neonatal period, approximately 40% subsequently exhibited neurological sequelae, and approximately 40% were found to be normal. In later series, although direct comparisons are hindered by differences in selection criteria, the outcome was somewhat better. Among term infants, only approximately 10% died in the neonatal period, and approximately 75% (i.e., nearly 85% of survivors) were normal on follow-up. The likelihood of neurological sequelae in infants after hypoxic-ischemic insult without a neonatal neurological syndrome is not known absolutely. The regionalization of both perinatal and pediatric care in the area served by Brown and co-workers11 allowed these investigators to conclude that such an occurrence was very unlikely. A similar conclusion can be drawn from a later study.55 Although more data are needed on this issue, the available information suggests that the occurrence of neonatal neurological features provides the best indicator of infants at risk for subsequent significant neurological deficits. However, these issues will require systematic reconsideration in the current era of hypothermia treatment.

Specific Aspects rate of death or subsequent neurological deficits was 42% with delayed onset of breathing for 1 to 9 minutes, 56% for 10 to 19 minutes, and 88% for more than 20 minutes. An additional prognostic feature of the first 30 minutes of life in asphyxiated term infants with severe fetal acidemia (umbilical arterial pH ≤ 7.0) is the occurrence of hypoglycemia.82 Thus, the 15% of acidemic infants in this study with an initial blood glucose of 40 mg/dL or lower had an 18.5-fold increased risk for death or moderate to severe encephalopathy than those with a glucose concentration higher than 40 mg/dL. A recent study of more than 300 term infants with apparent intrapartum asphyxia and HIE identified three key variables that together provided a strong prediction of a serious adverse outcome (death or severe neurological sequelae) (Table 20.23).421 The data suggested that the combination of need for chest compressions for more than 1 minute, a base deficit of 16 or greater, and age at onset of respiration at 30 minutes or greater was associated with a 93% risk of serious adverse outcome. The findings could be useful not only for early prognostication but also perhaps for decision-making concerning neuroprotective therapies. The additions of pH and arterial carbon dioxide pressure (PCO2) of cord blood gas measurements also provide predictive accuracy.422

Neonatal Neurological Syndrome The occurrence of a recognizable neonatal neurological syndrome after signs of intrauterine asphyxia (see earlier) is the single most useful indicator that a significant hypoxic-ischemic insult to the brain has occurred. Studies completed since the

Certain aspects of the neonatal neurological syndrome particularly useful in estimating the prognosis include the severity of the syndrome, the presence of seizures, and the duration of the abnormalities. Before discussing these specific neurological aspects, it is important to recognize that certain aspects of the non-neurological evaluation may provide prognostic information. Thus, in a study of asphyxiated infants (defined by depressed Apgar scores or fetal acidosis or both), of the 22 term infants with normal urine output, the mortality rate was approximately 5%, and neurological sequelae occurred in only 10% of survivors, whereas, with oliguria persisting beyond 24 hours of life, the mortality rate was 33%, and neurological sequelae occurred in 67% of survivors.426 A similar relationship between the severity of renal injury and an unfavorable neurological outcome was shown in the preterm infants. However, as also observed by others, neurological abnormalities in the neonatal period and on follow-up can occur in the absence of apparent renal injury (see the earlier section on neurological syndrome).53,425,426 The severity of the neonatal neurological syndrome is of major value. Thus, when systematically quantitated, the severity correlated directly with the incidence of neurological sequelae.b The studies of Finer and co-workers,20,394,431 which involved 226 full-term infants with HIE, and of Thornberg and co-workers, a References 11, 14-17, 20, 23, 25, 29, 55, 70, 250, 278, 327, 394, 402, 419, 420, and 423-444. b References 17, 23, 29, 55, 84, 250, 278, 327, 394, 419, 420, 424, 427, 428, 430-432, 437, 439-442, 444, and 445.

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TABLE 20.24  Outcome of Term Infants With HIE as a Function of Severity of Neonatal Neurological Syndromea

SEVERITY OF NEONATAL SYNDROMEb Mild Moderate Severe All

PERCENTAGE OF TOTAL

NO. OF PATIENTS

DEATHSc (%)

NEUROLOGICAL SEQUELAE (%)d

NORMAL (%)

115 136 40 291

0 5 8 13

0 24 20 14

100 71 0 73

a

Derived from 291 full-term infants with HIE. Mild, “hyperalert, hyperexcitable; normal muscle tone, no seizures”; moderate, “hypotonia, decreased movements, and often seizures”; severe, “stuporous, flaccid, and absent primitive reflexes.” c Includes in-hospital and postdischarge deaths. d Principally spastic motor deficits and cognitive disturbances. HIE, Hypoxic-ischemic encephalopathy. Data from Robertson C, Finer N. Term infants with HIE: outcome at 3.5 years. Dev Med Child Neurol. 1985;27:473–484; and Thornberg E, Thiringer K, Odeback A, Milsom I. Birth asphyxia: incidence, clinical course and outcome in a Swedish population. Acta Paediatr. 1995;84:927–932. b

TABLE 20.25 Seizures as an Unfavorable Prognostic Sign in Neonatal Hypoxic-Ischemic Encephalopathy in Term Infantsa Seizures increase the risk of neurological sequelae by as much as 40-fold Seizures persistently recalcitrant to anticonvulsant treatment are nearly uniformly associated with death or subsequent neurological deficits Early onset of seizures increases the risk of adverse outcome, and the risk is approximately 75% with onset in the first 4 h a

See text for references.

which involved 65 such infants, demonstrated this point clearly (Table 20.24).55 Although the overall incidence of death or neurological sequelae was 27%, infants with a mild neonatal syndrome had no subsequent deficits, whereas those with a severe syndrome uniformly either died (80%) or exhibited sequelae (20%). Prolonged follow-up is important; in one report of teenage outcome among term infants with moderate neonatal encephalopathy and considered normal on earlier assessment (n = 28), the majority exhibited some learning problems or behavioral disturbances, or both, at the later evaluation.444 Later neurodevelopmental follow-up has also identified some disability in infants that had mild neonatal encephalopathy. In one population of infants with mild HIE (n = 34), followed to 9 years, lower mean IQ (98.6 vs. 109 [P = 0.21]), increased thought problems (P = 0.001), and impaired motor assessment and manual dexterity (P = 0.002) were observed.446-448 The presence of seizures as part of the neonatal neurological syndrome increases the risk for neurological sequelae (Table 20.25).a The incidence of neurological sequelae in infants with seizures is as much as 40-fold greater than the incidence in

a References 14, 15, 20, 29, 53, 55, 70, 419, 420, 425, 430, 432, 435, 439, 440, 442, and 449-453.

those without seizures. Thus, in one series of 27 infants with HIE complicated by seizures, death, or subsequent neurological deficits occurred in 67%.55 Moreover, neurological sequelae are more likely if seizures occur in the first 12 hours or are difficult to control. For example, in one series of 45 infants, 76% with seizure onset at 4 hours of age or less died or exhibited neurological sequelae.420 In another study of 68 term newborns with apparent HIE, the combination of a neonatal neurological syndrome and seizures on the first day of life predicted abnormal outcome with 94% specificity and 72% sensitivity.442 The degree to which the seizures per se contribute to the poorer outcome in certain cases (see Chapter 12) or simply reflect a more serious insult is unresolved. The duration of neonatal neurological abnormalities is useful in identifying the infant at greatest risk for sequelae.a In two large series, essentially all infants who exhibited no neurological abnormalities after about 1 week of life (or on “discharge from the hospital”) were normal on follow-up.20,70 In a more recent series of 84 infants, approximately 90% of those with a normal examination at 7 days were normal on follow-up, and 10% had only mild abnormalities.439 In another careful study of 23 severely asphyxiated infants, all 17 infants who were normal on follow-up exhibited neurological signs for less than 2 weeks.70 Our experience is similar. Thus, the duration of neurological abnormalities is a good indicator of the severity of hypoxic-ischemic injury, and the disappearance of abnormalities by 1 or 2 weeks is an excellent prognostic sign. However, such analyses do not include systematic evaluation at school age; therefore, the possibility of learning disturbances cannot be conclusively ruled out.

Results of Neurodiagnostic Techniques Because outcome clearly relates to the severity of the neuropathology, any specialized technique that defines the extent of brain injury in the newborn period should provide valuable information regarding prognosis. Such techniques include electrophysiological measures, especially EEG, but also

a

References 20, 70, 414, 432, 433, and 439.

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy

TABLE 20.26 Electroencephalographic Patterns of Prognostic Significance in Asphyxiated Term Infantsa Associated with favorable outcome Mild depression (or less) on day 1 Normal background by day 7 Associated with unfavorable outcome Predominant interburst interval >20 s on any day Burst-suppression pattern on any day Isoelectric tracing on any day Mild (or greater) depression after day 12 a

See text for references. Associations with favorable or unfavorable outcome are generally 90% or greater, but the clinical context must be considered.

541

TABLE 20.27 Predominant Interburst Interval Duration in Prediction of Outcomea Predominant interburst interval duration is obtained readily by manual measurement of the predominant interval accounting for more than 50% of all interburst interval durations A predominant interburst interval duration of more than 30 s is associated with an unfavorable outcome in 100% of cases, a duration of more than 20 s is associated with an unfavorable outcome in 92% of cases, and an interval lasting longer than 10 s is associated with an unfavorable outcome in 72% of cases The predominant interburst interval duration is more useful than the burst-suppression periodic pattern because the latter accounts for a small minority of discontinuous tracings a

evoked potentials, brain imaging methods, and methods to evaluate cerebral hemodynamics and metabolism.

Electroencephalography and Evoked Potentials As discussed in the diagnosis section, specific EEG patterns are indicative of particular types of hypoxic-ischemic brain injury (see Table 20.11). Such information, especially when coupled with imaging data, is valuable for prognostic assessment (see earlier). The severity of EEG abnormalities and their duration in the asphyxiated infant also are of prognostic importance (Table 20.26).a Regarding severity, in the term infant the most common feature is a continuous or intermittent discontinuity of EEG (see Chapters 10 and 12). The most extreme of these discontinuous tracings is the burst-suppression pattern, which is associated with a very high likelihood of an unfavorable outcome, especially when the tracing is non-reactive (see Chapter 10). However, burst-suppression tracings account for a minority of excessively discontinuous neonatal EEG tracings. We have found that a relatively simple means of quantitation of excessively discontinuous tracings in the term infant (i.e., analysis of the duration, in 10-second blocks, of the predominant IBI) has major prognostic value (Table 20.27).190 Predominant IBI durations of more than 30 seconds were invariably associated with an unfavorable outcome, and durations of more than 20 seconds were associated with an unfavorable outcome in 92%. Notably, predominant IBI durations of more than 10 seconds still predicted abnormal outcome in 72%. Of the 43 discontinuous tracings studied, only 7 (16%) exhibited a burst-suppression pattern, as defined classically (see Table 20.27 and Chapter 10). Thus, the predominant IBI duration, readily quantitated at the bedside, was highly effective and, critically, applicable to most excessively discontinuous tracings in the term newborn with encephalopathy. Regarding the duration of EEG abnormalities, as with the neonatal neurological syndrome, recovery of normal EEG background by day 7 is associated with a favorable outcome (see Table 20.26). In one large series of 77 term infants with apparent HIE and studied at 7 days of age, of 52 with a normal EEG tracing, 83% were later (at 1 year of age) found to be normal, 17% had mild abnormalities, and none had severe abnormalities.439 a References 70, 160, 169, 170, 173, 175, 176, 178, 180-184, 187, 190, 439, and 453-455.

See text for details and Chapter 4.

TABLE 20.28 Value of Amplitude-Integrated Electroencephalography in Assessment of Asphyxiated Term Infantsa Detection of severe abnormalities (i.e., CLV, FT, BSP) in the first hours of life has a positive predictive value of an unfavorable outcome of 80%–90% Severe abnormalities may improve within 24 h (≈50% of BSP and 10% of CLV/FT) Rapid recovery of severe abnormalities is associated with a favorable outcome in 60% of cases The combination of early neonatal neurological examination and early aEEG enhances the positive predictive value and specificity a

See text for references. aEEG, amplitude-integrated encephalography; BSP, burst-suppression pattern; CLV, continuous low voltage; FT, flat trace.

Consistent with earlier work, studies in the era of therapeutic hypothermia show that the early return of sleep-wake cycling and the normalization of background EEG abnormalities are good prognostic indicators.192,456 The link between timing of this evolution and prognostic ability can be altered by therapeutic hypothermia, so that delayed recovery may still be associated with a normal outcome.201 A normal EEG recorded soon after birth is highly associated with a normal outcome at 2 years.457 However, an abnormal EEG soon after birth may recover over subsequent days, but if it remains abnormal at 48 hours a poor prognosis is highly likely.457 aEEG has been of considerable value in the estimation of prognosis in the asphyxiated term newborn (Table 20.28).191-196,198,227,454,458 As described earlier in Chapters 10 and 12, the most useful tracings for detection of severe encephalopathy have been continuous low-voltage, flat, and burst-suppression patterns. Because PPVs for such tracings in the first hours of life are 80% to 90%, aEEG has been valuable for early selection of infants for neuroprotective therapies (e.g., hypothermia; see later). Notably, 10% to 15% of infants with these marked background abnormalities may normalize within

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TABLE 20.29 Prognostic Value of Visual- and Somatosensory-Evoked Potentials in Term Infants With HypoxicIschemic Encephalopathy (<6 Hours of Age)

RESULT OF EVOKED POTENTIALS Somatosensory Normal Delayed No response Visual Normal Delayed No response

TOTAL NO.

NORMAL

12 8 14 12 14 8

OUTCOME SEQUELAE

DEATH

11 4 0

0 2 0

1 2 14

10 5 0

2 0 0

0 9 8

Data from Eken P, Toet MC, Groenendaal F, De Vries LS. Predictive value of early neuroimaging, pulsed Doppler and neurophysiology in full-term infants with hypoxicischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed. 1995;73:F75–F80.

24 hours. Rapid recovery is associated with a favorable outcome in 60% (see Table 20.28). Importantly, although aEEG in the first 6 hours is slightly superior to the neonatal neurological examination in identifying infants with an unfavorable outcome, the combination of aEEG and the neurological examination is more nearly optimal, with a specificity of 94%.194 The positive predictive value of a severely abnormal aEEG for death or disability at 6 hours is approximately 0.60, and this value declines slightly, but not significantly, in cooled infants.457,459 Serial visual-evoked potentials carried out in term asphyxiated infants have been shown to provide valuable prognostic information.356,460,461 In one study of 34 full-term infants with HIE who were studied within 6 hours of delivery, the finding of normal visual-evoked potentials was associated with a normal neurological outcome in 10 of 12 infants, whereas no response to visual input was followed by death in 8 of 8 infants (Table 20.29).227 However, the 14 infants with delayed latencies had an intermediate outcome. Serial somatosensory-evoked potentials also have been shown to provide valuable prognostic information in assessment of the asphyxiated infant.227,462-467 In 20 survivors of asphyxia at term, all 13 infants with normal outcome had normal somatosensory-evoked response by 4 days of age, whereas the 7 infants with subsequent deficits had abnormal or absent responses beyond 4 days.464 One study of 34 term infants with HIE who were evaluated within 6 hours of delivery showed striking predictive value for favorable or unfavorable outcomes with normal potentials or no response, respectively (see Table 20.29).227 Moreover, compared with the results with visual-evoked potentials, fewer infants had intermediate abnormalities on somatosensory-evoked potential testing (see Table 20.29).227 Thus, the data suggest that somatosensory-evoked potentials could be useful for early prognostic formulations.

Ultrasound In the term infant, as discussed earlier (see the section on diagnosis), major injury to basal ganglia and thalamus and focal and multifocal ischemic parenchymal lesions have been identified and have contributed to prediction of outcomes. However, most scans do not show such discrete lesions.468,469 In one careful study of 40 term infants with HIE and cranial ultrasonography in the first week, 13 of 14 infants (93%),

with either a normal scan or with isolated germinal matrix or intraventricular or subarachnoid hemorrhage, were normal on follow-up.226 Of the remaining infants, the ultrasonographic findings nearly consistently associated with subsequent neurological deficits were bilateral abnormalities of basal ganglia in 9 infants, focal parenchymal echodensities or apparent stroke in 8, or a featureless appearance with patchy echodensities in 7. Periventricular echodensities may occur in the asphyxiated term infant, as in the preterm infant, but they are generally observed uncommonly. Confusion sometimes exists concerning the finding in the asphyxiated term infant of small ventricles or those that cannot be visualized. Whereas this observation has been said to be indicative of major brain edema,469 in another study this finding was present in 62% of control subjects in the first week of life and could not be clearly related to structural disease.468 In the latter study, the finding of a normal ultrasound scan in 9 of the 32 term infants with HIE was followed by a normal outcome in 8 of the 9 infants.468

Magnetic Resonance Imaging Because the likelihood, nature, and severity of subsequent neurological deficits in the infant with HIE are related most decisively to the extent and specific topography of the lesions, MRI should prove to be the best imaging modality for determining prognosis. Studies of term infants support this prediction.a Particularly vivid examples of the value of neonatal MRI in establishing prognosis were discussed earlier and include those infants with evidence of selective neuronal necrosis of the major varieties defined in Chapter 18 (i.e., the diffuse type, the cerebral–deep nuclear type, and the deep nuclear–brain stem type). Of all imaging modalities currently applied to the newborn, only MRI provides consistent delineation, particularly of involvement of specific areas of the cerebral cortex, basal ganglia, thalamus, and brain stem, as well as the cerebral white matter. The relation of motor and cognitive outcomes to topography of injury delineated by neonatal MRI can be summarized generally as follows. Infants with normal MRI findings generally do not exhibit major motor or cognitive deficits.28,29,282 a References 29, 61, 226, 236, 237, 240, 241, 245, 247-250, 253, 256, 258, 296, 348, 362, 386, and 470-472.

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy 30-month mental development index by pattern of injury 120

30-month MDI

100

80

60

40 Normal

A

Watershed

Basal ganglia/ thalamus

30-month neuromotor score by pattern of injury

30-month neuromotor score

5 4 3 2 1 0

B

Normal

Watershed

Basal ganglia/ thalamus

Figure 20.23  Relationship between predominant regions injured and neurological outcome. Predominant regional patterns were obtained by magnetic resonance imaging (MRI) in 173 term infants with encephalopathy, most probably resulting from hypoxia–ischemia. The relative distribution of MRI patterns was “parasagittal watershed” (n = 78), “basal ganglia/thalamus” (n = 44), or “normal” (n = 51). (A) Box plot of the 30-month Mental Development Index (MDI) by the pattern of injury. The MDI was lowest in the infants with the basal ganglia/thalamus predominant pattern, with intermediate scores in infants with the watershed pattern (P = .0007). The thick line represents the median, with the 25th and 75th percentiles as the lower and upper limits of the box; whiskers indicate the 5th and 95th percentiles. The dashed line indicates the lowest attainable MDI score. (B) Box plot of the 30-month neuromotor score by the pattern of injury. Neuromotor impairments were most severe in the infants with the basal ganglia/thalamus pattern (P = .0001). (From Miller SP, Ramaswamy V, Michelson D, et al. Patterns of brain injury in term neonatal encephalopathy. J Pediatr. 2005;146:453–460.)

Infants with prominent basal ganglia/thalamic (BG/T) lesions have the poorest motor and cognitive outcomes. A particularly useful predictor of prominent subsequent motor deficits (i.e., cerebral palsy) is MRI evidence of severe BG/T injury and abnormal signal in the posterior limb of the internal capsule (PLIC) (Fig. 20.23).248,275,276,296,473-475 In a well-studied series of 175 infants with neonatal HIE and BG/T lesions, a striking relationship was apparent between the severity of the lesions, the presence of an abnormal PLIC signal, and cerebral palsy in survivors (Fig. 20.23 from Volpe). With mild lesions (n = 28), the PLIC signal was abnormal in none,

543

equivocal in 4, and normal in 24; only 3 of the 24 infants (12%) developed cerebral palsy. However, with severe BG/T lesions (n = 63), the PLIC signal was abnormal in 62—all of whom developed cerebral palsy. The severity of BG/T lesions also provides information regarding other neurological outcomes (Figs. 20.24 to 20.27). Infants with predominant parasagittal watershed lesions have more prominent cognitive than motor deficits (see earlier). In this group especially, cognitive deficits may occur without appreciable motor deficits.a Infants with the quantitatively unusual but distinctive pattern of injury to BG/T and brain stem tegmentum, which is common after severe sentinel events, have the highest likelihood of death. Mortality rates are as high as 35%.276,282,348 Infants with predominantly cerebral white matter injury, present in only approximately 15% of term infants with HIE, exhibit cognitive deficits more than motor deficits. Important contributing factors in pathogenesis include late preterm gestational age, neonatal hypoglycemia, and chronic hemodynamic instability, similar to congenital heart disease.282,285 Combining the findings of BG/T injury and abnormalities in the PLIC, Martinez-Biarge and co-workers developed algorithms for outcomes.275 The severity of the BG/T and PLIC lesions is shown in Fig. 20.24. The algorithms for outcomes of mild (see Fig. 20.25), moderate (see Fig. 20.26), and severe injury (see Fig. 20.27) are shown. A large meta-analysis evaluated 32 studies of MRI in 860 non-cooled infants with neonatal encephalopathy. 341 Conventional MRI, mostly using scoring systems based on T1- and T2-weighted imaging, had a pooled sensitivity of 0.91 and specificity of 0.51 to predict adverse outcome (death and/or moderate/severe disability, depending on the individual study) at 12 or more months of age. Late MRI (defined as MRI between day 8 and 30 of life) had higher sensitivity but lower specificity than early MRI (performed between day 1 and 7 of life). However, there was significant statistical heterogeneity between studies. Hypothermia does not appear to alter the prognostic value of MRI, although two studies showed that it may alter the timing of changes seen on MRI (see Fig. 20.15).303 Another prospective study using serial MRI found that the T1/T2 changes appeared later (by day 3 of life in noncooled infants, but not until the MRI on day 10 of life in 2 of the cooled infants).261 Despite these limitations, recent analyses showed that predictive values of MRI do not seem to be affected by therapeutic hypothermia. Rutherford and colleagues studied 131 infants from the TOBY (TOtal Body hYpothermia) cooling trial476 and found that in the infants treated with therapeutic hypothermia, fewer BG/T lesions and fewer abnormalities in the PLIC were identified in comparison to noncooled infants. Infants who were cooled were more likely to have normal scans. The ability of major MRI abnormalities to predict death or major disability at 18 months was almost identical in both groups (cooled infants, sensitivity 0.88, specificity 0.82, PPV 0.76, and negative predictive value (NPV) 0.91; non-cooled group, sensitivity 0.94, specificity 0.68, PPV 0.74, and NPV 0.92). In the Infant Cooling Evaluation (ICE) trial, fewer newborns in the hypothermia group had moderate/severe white matter or gray matter abnormalities

a

References 29, 274, 281, 282, 388, and 389.

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Unit IV  Hypoxic-Ischemic and Related Disorders

A

B

C

Figure 20.24  Top row: Axial T1-weighted images showing: (A) mild basal ganglia/thalamic (BG/T) lesions (arrow); (B) moderate BG/T injury (arrows); (C) severe BG/T abnormalities (circled). Bottom row: Axial T1-weighted images showing: (A) normal signal intensity (SI) in the posterior limb of the internal capsule (PLIC) (arrow); (B) equivocal, asymmetrical and slightly reduced SI in the PLIC (arrow); and (C) abnormal, absent SI in the PLIC (arrow). (Courtesy of Martinez-Biarge M, Diez-Sebastian J, Rutherford MA, Cowan FM. Outcomes after central grey matter injury in term perinatal hypoxic-ischaemic encephalopathy. Early Hum Dev. 2010;86:675–682.)

on T1/T2-weighted scans as compared with infants in the normothermia group; but abnormal MRI findings were still predictive of outcome in both the normothermia and the hypothermia groups.477 The sensitivity of T1/T2 and diffusion abnormalities to predict adverse outcome was low (0.27 to 0.60) but specificity was high (0.92 to 0.95). In the National Institute of Child Health and Human Development cooling trial, the sensitivity, specificity, PPV, and NPV of moderate/severe brain injury on neonatal MRI to predict death or IQ less than 70 at 6 to 7 years of age were similar between the hypothermia group (0.77, 0.85, 0.71, and 0.89, respectively), and the control group (0.85, 0.66, 0.69, and 0.83, respectively).396 Death or IQ less than 70 occurred in 4 of 50 children with normal MRI in the neonatal period. A recent systematic review478 has analyzed MRI studies in detail and determined the pooled sensitivity, specificity, PPV, and NPV as follows: DWI: ≤1 wk: sensitivity 0.58 and specificity of 0.89; apparent diffusion coefficient (ADC) at ≤1 wk: sensitivity 0.79 and specificity 0.85; T1/T2: ≤1 wk: sensitivity 0.84 and specificity 0.90, ≤2 wk: sensitivity 0.98 and specificity 0.76, ≤6 wk: sensitivity 0.83 and specificity 0.53.

Thus, MRI remains a very powerful tool in the prognosis of an infant with HIE with or without therapeutic hypothermia.

Magnetic Resonance Spectroscopy MR spectroscopy of both the proton and phosphorus types has been useful in determination of outcome in neonatal hypoxic-ischemic disease in the term newborn. The data should be interpreted in the context of the findings in experimental models of an early increase in cerebral lactate, detectable by proton MR spectroscopy, preceding a “secondary delayed energy failure,” characterized by a decline in high-energy phosphate compounds, detectable by phosphorus MR spectroscopy (see Chapter 10). (The primary, initial energy failure occurs close to the time of the initial insult, usually in utero and before any measurements can be made.) Studies by proton MR spectroscopy performed in the first several days of life showed distinctly elevated cerebral lactate in asphyxiated human infants.a The elevation in lactate is apparent a

References 313, 318-321, 323, 326-328, 330-339, and 475.

Mild BG/T

Cerebral palsy 10%–15% (only mild-moderate impairment) Equivocal PLIC

Normal PLIC

2/3 walking at 2 years, some may start late

Walking at 2 years

Feeding

Speech and language

Vision

DQ

Seizures

Look at the cortex 10% may have some mild feeding problems No need for a gastrostomy

25% may have some speech problems; in most cases mildmoderate.

The probability of visual impairment is very low, unless there is extensive white matter injury.

>84 in 80% and >70 in 90% especially if PLIC normal Normal or mild: 3%–6% Moderate: 11% Severe: 19%

Figure 20.25  Flow chart showing patterns of outcome with mild basal ganglia/thalamic (BG/T) injury. DQ, developmental quotient; PLIC, posterior limb of the internal capsule. (Courtesy of Martinez-Biarge M, Diez-Sebastian J, Rutherford MA, Cowan FM. Outcomes after central grey matter injury in term perinatal hypoxicischaemic encephalopathy. Early Hum Dev. 2010;86:675–682.) Moderate BG/T

Look at the PLIC Equivocal PLIC

Abnormal PLIC

Cerebral palsy 60% Mostly mild (75%) 2/3 will be walking, may start late

Cerebral palsy 75% Moderate (50%) or severe (40%) 70%–80% will not walk at 2 years

Feeding

Speech and language

Vision

DQ

Seizures

Look at the cortex 40%–50 % may have some feeding problems, but fewer than 10% will need a gastrostomy

Most children will have some speech problems; severe in 25%

20%–55% will have some visual impairment, depending on the severity of white matter and brain stem injury

50%–75% of children are assessable, up to 35% of them will have a DQ <70 Normal or mild: 3%–6% Moderate: 11% Severe: 19%

Figure 20.26  Flow chart showing patterns of outcome with moderate basal ganglia/thalamic (BG/T) injury. DQ, developmental quotient; PLIC, posterior limb of the internal capsule. (Courtesy Martinez-Biarge M, Diez-Sebastian J, Rutherford MA, Cowan FM. Outcomes after central grey matter injury in term perinatal hypoxic-ischaemic encephalopathy. Early Hum Dev. 2010;86:675–682.)

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Unit IV  Hypoxic-Ischemic and Related Disorders Severe BG/T

Cerebral palsy 98% Mostly severe (95%)

Feeding

Speech and language

90% will have some feeding problems.

95% will have some speech problems, severe in most

Gastrostomy

Vision

50%–75% will have some grade of visual impairment, especially with moderate-severe white matter and brain stem injury

Look at the pons

DQ

Seizures

Children are in general difficult to assess because of their motor impairment at this age

Look at the cortex

Normal: 25%–30% Mild: 45%–50% Moderate: 60% Severe: 75%

Normal: 35% Moderate: 50% Severe: 90% Figure 20.27  Flow chart showing patterns of outcome with severe basal ganglia/thalamic (BG/T) injury. DQ, developmental quotient. (Courtesy Martinez-Biarge M, Diez-Sebastian J, Rutherford MA, Cowan FM. Outcomes after central grey matter injur y in term perinatal hypoxic-ischaemic encephalopathy. Early Hum Dev. 2010;86:675–682.)

in the first 18 hours of life and, importantly, correlates with the severity of the delayed secondary energy failure observed on subsequent days (see Fig. 20.20B), the neonatal neurological syndrome, and the neurological outcome (Fig. 20.28).318,326-328,339 Infants with the poorest outcomes have persistently elevated lactate levels (i.e., for several weeks or more),313,314,324 whereas those with favorable outcomes had resolution of lactate elevations during this interval. NAA, a marker of the neuronal-axonal unit as well as oligodendroglial precursors and immature oligodendrocytes,479,480 is usually only variably affected during these early phases.a However, a decline in NAA does become apparent after many days to weeks as tissue loss becomes established. Thayyil and colleagues pooled 10 studies that evaluated the Lac/NAA ratio in the basal ganglia, with a median cut-off value between normal and abnormal of 0.29.341 The pooled sensitivity was 0.82 and specificity was 0.95 for a value greater than 0.29 to predict a poor outcome (death or disability measured at ≥12 months). These investigators considered the Lac/NAA ratio

a

References 320, 322, 325, 327-329, 332-334, 336, 338, 475, and 481.

in the deep nuclear gray matter to be the most accurate MR spectroscopy biomarker for prediction of outcome. MR spectroscopy also appears to be valuable in prognostication in the hypothermia era. Corbo and colleagues evaluated 38 infants with birth asphyxia,482 half of whom were cooled. There were lower levels of Lac in the infants treated with hypothermia, but the NAA ratios were not different between the two groups. Ancora and colleagues483 followed to 2 years of age, 20 newborns who were treated for HIE with selective head cooling and had MRI in the neonatal period. NAA/Cr in the basal ganglia (value ≤0.67) had a PPV of 1.0 and NPV of 0.93 to predict poor outcomes (death or severe cerebral palsy at 2 years of age). Studies by phosphorus MR spectroscopy performed in the first week of life show a delayed secondary decline in high-energy phosphate compounds in asphyxiated human infants.308,309,311,312 This decline becomes apparent generally on the second day of life and reaches a nadir at 2 to 4 days of life. The severity of this delayed secondary energy failure correlates with the severity of both the neonatal neurological syndrome (see Fig. 20.19) and the subsequent neurological deficits (Fig. 20.29).311,312 As noted earlier, the sustained alkaline intracellular pH identified

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy

MR spectroscopy, is adapted readily to clinically used MR instruments. Thus, although the data obtained by phosphorus MR spectroscopy have provided important information, it is likely that future work will continue to be carried out primarily with proton MR spectroscopy.

4

Lactate/creatine

3

Computed Tomography

2

1

0 Normal outcome

Adverse outcome

Control

Figure 20.28  Relation between the lactate/creatine ratio obtained by proton magnetic resonance spectroscopy in the first 18 hours of life, and the neurological outcome. Median, interquartile ranges, and upper and lower adjacent values of the ratios in infants with normal outcome, infants with abnormal outcome, and control infants are shown. The value for infants with adverse outcome was significantly different from the values for both infants with normal outcome and control infants. (From Hanrahan JD, Cox IJ, Azzopardi D, et al. Relation between proton magnetic resonance spectroscopy within 18 hours of birth asphyxia and neurodevelopment at 1 year of age. Dev Med Child Neurol. 1999;41:76–82.)

PCr/Pi SDS

547

4 3 2 1 0 –1 –2 –3 –4 –5 –6 –7 –8

Although MRI has the greatest predictive capability and is the preferred imaging modality, historically, CT in the neonatal period has provided adjunctive information of prognostic value. As noted in the section on diagnosis, in infants with major injury to the basal ganglia and thalamus, to a considerable extent CT defines the site and extent of the lesion and allows estimation of the neurological sequelae outlined in the section on clinicopathological correlations. More often, however, the CT appearance in the infant with HIE cannot be so neatly categorized. In the term infant, several earlier series categorized the CT findings as normal or showing variable degrees of hypoattenuation or hemorrhage, or both.423,484-488 At the extremes of injury, CT scans can be of some assistance. Infants with normal CT scans will rarely exhibit severe neurological deficits on follow-up, and infants with scans demonstrating severe abnormalities, such as marked diffuse hypodensity, rarely are normal on follow-up. Moreover, those unusual infants with major degrees of intracerebral hemorrhage, usually indicative of hemorrhagic infarction, almost always exhibit neurological deficits on follow-up. However, in several reported series, as many as one-third of infants with less severe degrees of hypoattenuation had no intraparenchymal hemorrhage; in this group, the outcome is variable and not readily predicted. Nevertheless, it is apparent that in more than one-half of term infants with HIE, the CT scan provides some useful prognostic information. This proportion may be increased by a follow-up CT study at 2 to 6 weeks of age, when initially ambiguous findings may evolve to either a normal or an overtly abnormal scan.486

Measurement of Cerebral Blood Flow Velocity, Cerebral Blood Volume, or Cerebral Blood Flow Normal

Impairment

Without disability

Dead

With disability

Figure 20.29  Relation between phosphocreatine/inorganic phosphate (PCr/Pi) standard deviation score (SDS), determined by phosphorus magnetic resonance spectroscopy (during the period of secondary energy failure) as a number of standard deviations from the mean of control values, and neurodevelopmental outcome, determined by evaluation at 4 years in 62 asphyxiated infants. Open circles represent term average for gestational age (AGA) infants, closed circles represent term small for gestational age (SGA) infants, closed triangles represent preterm AGA infants, and closed squares represent preterm SGA infants. (From Roth SC, Baudin J, Cady E, et al. Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years. Dev Med Child Neurol. 1997;39:718–725.)

by phosphorus MR spectroscopy also correlates with poor neurodevelopmental outcome.314 Currently, proton MR spectroscopy is used much more widely than phosphorus MR spectroscopy in the evaluation of newborn infants, because this approach, unlike phosphorus

Although not commonly used for the assessment of brain injury and the estimation of outcome in neonatal HIE, measurements of CBF velocity, cerebral blood volume and CBF have provided useful prognostic information. A series of studies has established that the postasphyxial human newborn exhibits a state of vasoparalysis and cerebral hyperemia, which is detectable as increased CBF velocity and decreased cerebrovascular resistance by Doppler studies, as increased cerebral blood volume by near-infrared spectroscopy, and as increased CBF by xenon-133 clearance or PET (see Chapter 13). These changes are correlated with the degree of brain injury, as discussed next. Measurements of CBF velocity by the Doppler technique at the anterior fontanelle have provided useful prognostic information in full-term asphyxiated infants studied in the first days of life. Determination of CBF velocity in such infants generally, from approximately 1 to 6 days after the insult, showed an increase in mean flow velocity with decreased resistance indices (i.e., cerebral vasodilation).489-498 One large study involved 39 term asphyxiated infants with “postasphyxial encephalopathy” in whom Doppler measurements from the anterior cerebral artery from the first hour delineated distinct abnormalities at a median

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Unit IV  Hypoxic-Ischemic and Related Disorders

age of 26 hours (i.e., increased CBF velocity and decreased Pourcelot resistance index).494 This constellation suggested a state of cerebral hyperemia with vasodilation, leading to both decreased resistance and increased flow. The mechanism underlying this “delayed hyperemia” is unclear (see Chapter 13). The cerebral hyperemia could account in part for the increase in intracranial pressure (ICP) sometimes observed at this time in severely asphyxiated infants (see Chapter 19). An important point for this discussion is that the changes were correlated with unfavorable outcome. Thus, no infant with CBF velocity greater than 3 standard deviations above the mean survived without severe neurological impairment.494 One report showed that the increased CBF velocity in infants with an unfavorable outcome is not apparent until 12 to 24 hours of age, and thus earlier measurements do not have appreciable prognostic value.498 Similar measurements on infants subjected to therapeutic hypothermia have not been reported. That the Doppler measurements reflected cerebral vasodilation, at least in part, was shown in studies of similar infants by near-infrared spectroscopy.499-501 Such studies of asphyxiated human infants on the first day of life suggested an increase in both cerebral blood volume and CBF. Moreover, other work with near-infrared spectroscopy showed that the state of cerebral hyperemia is accompanied by evidence of diminished oxygen extraction and elevated cerebral venous oxygen saturation, perhaps reflecting tissue injury.502 Several investigators have attempted to use near-infrared spectroscopy measurements for both short- and long-term outcomes in infants after birth asphyxia with limited success to date. One study showed that infants with HIE (n = 12) who had a poor outcome (death, cerebral palsy, or global delays at 12 months) had a higher level of cerebral oxygenation, measured as tissue oxygenation index at 12 hours of age, than infants with a normal outcome.503 A related study reported similar findings in 22 term infants with HIE in which in the first day of life the tissue oxygenation index was 80% in infants with abnormal outcomes at 1 year versus 75% in infants with normal 1-year outcomes (P = .04). A larger study (n = 39) in the era of therapeutic hypothermia again demonstrated that cerebral oxygenation was higher in newborns with an adverse outcome.504 Whether the use of near-infrared spectroscopy could provide valuable information for long-term prognostic estimation is not established by these short-term studies, but it seems possible. Decisive demonstration of both the prognostic value of direct measurement of CBF and of the likelihood that the studies using Doppler ultrasound and near-infrared spectroscopy reflected cerebral hyperemia was accomplished by direct measurements in asphyxiated infants by xenon-133 clearance and by PET.505,506 In the large series of infants studied by xenon clearance, infants with the poorest outcome had the highest values for CBF in the first day of life (see Chapter 13). Asphyxiated infants who died or had severe brain injury had mean CBF of 30.6 mL/100 g per minute; those who had moderate to severe brain injury had CBF of 15.1 mL/100 g per minute; and those with normal outcome had CBF of 9.2 mL/100 g/min. That the low Pourcelot resistance index shown by Doppler reflected cerebral vasodilation, presumably secondary to vasoparalysis, also was shown by Pryds and co-workers,505 who demonstrated no reactivity of flow to arterial blood pressure or arterial carbon dioxide tension (PaCO2) in the group with poorest outcome,

no reactivity to blood pressure (although retained reactivity to carbon dioxide) in the group with intermediate outcome, and retained reactivity to both pressure and carbon dioxide in the group with normal outcome. A later study of 16 term infants with HIE used PET to determine CBF primarily at 1 to 4 days of life and found higher flows in those infants with abnormal neurological outcome (35.6 mL/100 g/min) than in those with normal neurological outcome (18.3 mL/100 g/min).506 That these measures of cerebral hyperemia are not related to increased cerebral metabolic rate was shown by a study of 20 infants with HIE with PET measurements of cerebral metabolic rate for glucose.507 Thus, the total cerebral metabolic rate for glucose was inversely correlated with severity of the encephalopathy and the degree of neurological deficits. Those infants with the most severe deficits later had the lowest neonatal values of cerebral metabolic rate for glucose.

Conclusion No neurodiagnostic technique is capable of diminishing the importance of the clinical evaluation of the infant in assessment of outcome, although MRI appears to have the strongest prognostic capability of all the complementary technologies. In clinical practice, a combination of clinical history and examination, electrophysiology, and neuroimaging with MRI constitutes the best complete evaluation to enable the most accurate prognostication for the term infant with HIE.

MANAGEMENT Management of the term-born infant with HIE requires attention to the involvement of multiple systems. Although we will emphasize the neurological aspects of therapy, it is the rule rather than the exception that infants with HIE have disturbances of pulmonary, cardiovascular, hepatic, and renal functions as well. 54,60,63-65,426,508 The emphasis on management is in terms of the following: prevention of peripartum hypoxic-ischemic insult; recognition of peripartum hypoxic-ischemic insult; stabilization of systemic physiology, including respiratory, cardiovascular and metabolic; control of seizures; commencement of neuroprotective therapy; (therapeutic hypothermia), if indicated; and consideration of other potential neuroprotective intervention therapies (Table 20.30). Concerning all of these, it is important to note that the major portion of

TABLE 20.30 Basic Elements of the Management of Neonatal Hypoxic-Ischemic Encephalopathy Prevention of peripartum hypoxic-ischemic injury Recognition of peripartum hypoxic-ischemic injury Stabilization of systemic physiology, including respiratory, cardiovascular, and metabolic • maintenance of adequate ventilation • maintenance of adequate perfusion • maintenance of adequate glucose levels Control of seizures Commencement of therapeutic hypothermia, if indicated Consideration of other potential neuroprotective intervention therapies

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy

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neuronal death following hypoxic-ischemic insult evolves after termination of the insult (i.e., often during the time that the therapeutic maneuvers to be reviewed next are applied).

5. Consideration of electrophysiological monitoring to assess background cerebral activity during the first few hours of life. This assessment is accomplished readily with aEEG.

Prevention of Peripartum Hypoxic-Ischemic Insult

Stabilization of Systemic Physiology

A critical aspect of management is prevention of the hypoxic-ischemic insult, and because most infants appear to experience the primary insult in utero, prevention of intrauterine asphyxia is paramount (see Table 20.30). Detailed discussion of the management of pregnancy, labor, and delivery is beyond the scope of this book, but the basic elements of this aspect of management are summarized in Table 20.31 and are based on the considerations discussed in Chapter 17. The first goal is identification of the fetus being subjected to or likely to experience hypoxic-ischemic insults with labor and delivery. Thus, antepartum assessment (see Chapter 17) with identification of the high-risk pregnancy is central. The fetus should be monitored during the intrapartum period primarily by the electronic techniques described in Chapter 17, supplemented, when necessary, by fetal blood sampling to determine pH and blood gas values. The need for better methods to assess fetal neurological status, particularly fetal cerebral hemodynamics and metabolism, and placental functioning, was emphasized earlier. The particular mode of intervention for the fetus threatened by hypoxic-ischemic insult depends on a variety of factors related to the fetus and the mother, but often cesarean section is a critical intervention in the prevention of the degree of asphyxia that leads to brain injury.

This aspect of management relates to respiratory, cardiovascular, and metabolic status (see Table 20.30).

Recognition of Peripartum Hypoxic-Ischemic Injury The recognition of the risk factors for peripartum hypoxicischemic injury and the associated neurological syndrome associated with HIE can be challenging, as discussed earlier (see Tables 20.2 to 20.6). Thus, clinical suspicion must be high at all at-risk settings to fully evaluate the infant. This evaluation is accomplished best as part of a clinical practice guideline to standardize the approach of the clinical team to such infants and should consider inclusion of the following: 1. Evaluation for metabolic acidemia with cord blood gas measurement or infant blood gas measurement within 60 minutes of birth. 2. Optimal resuscitation and stabilization of the infant, as discussed later. 3. Avoidance of hyperthermia by the removal of external heat sources, such as overhead heating devices in the resuscitation room, until a clinical decision about the need for neuroprotective therapy is made. 4. Systematic serial neurological examination of the infant with a standardized neurological scoring system over the first few hours of life to define the presence and severity of any encephalopathy.

TABLE 20.31 Prevention of Peripartum HypoxicIschemic Injury Antepartum assessment and identification of the high-risk pregnancy Electronic fetal monitoring Fetal blood sampling Appropriate interventions (e.g., cesarean section)

Maintenance of Adequate Ventilation Maintenance of adequate ventilation is a central aspect of supportive care, an imprecise term that refers to the maintenance also of temperature, perfusion, and metabolic status. The importance of these various postnatal aspects of management cannot be overemphasized, although a significant intrauterine insult has occurred in most asphyxiated infants, postnatal disturbances of ventilation and perfusion particularly may play an important role in determining the ultimate severity of neurological injury. In this section, we discuss the particular importance of maintenance of adequate arterial concentrations of oxygen and carbon dioxide.

Oxygen Hypoxemia.  The avoidance of oxygen deprivation clearly is

a cornerstone of supportive therapy. Hypoxemia may lead to a disturbance of cerebrovascular autoregulation and, as a consequence, a pressure-passive circulation (Table 20.32; see Chapter 13). Under such circumstances, the infant is vulnerable to superimposed ischemic cerebral injury with only moderate decreases in arterial blood pressure. Indeed, this mechanism may be the most important by which hypoxemia leads to parenchymal injury. Provision of adequate oxygen also is necessary to prevent additional neuronal and white matter injury (see Table 20.32). The most common cause of serious persistent hypoxemia in the term infant, persistent pulmonary hypertension of the newborn, can be complex to manage. The risk for this condition may be elevated in the setting of therapeutic hypothermia. 509,510 It has also been suggested that the presence of this severe respiratory complication may further compromise the well-being of infants receiving hypothermia by leading to greater cerebral hypoxemia.511 The management of persistent pulmonary hypertension of the newborn is discussed in standard writings on neonatology. Suffice it to say here that the principal therapeutic modalities range from oxygen and assisted ventilation to the administration of pulmonary vasodilator drugs (e.g., nitric oxide), passive hyperventilation, and high-frequency ventilation.

TABLE 20.32 Deleterious Neurological Consequences of Disturbed Oxygenation Hypoxemia Pressure-passive cerebral circulation Neuronal and white matter injury Hyperoxia Cerebral vasconstriction Increased oxidative stress Neuronal and white matter injury Increased mortality

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Extracorporeal membrane oxygenation has been used for the most severe cases, although the advent of nitric oxide therapy decreased the need for this invasive approach considerably.

Hyperoxia.  Although hypoxemia is serious and requires

prompt reaction, overreaction also may be deleterious if hyperoxia is produced (see Table 20.32). Hyperoxia may lead to cerebral vasoconstriction or increased oxidative stress or both (see Chapters 13 and 16). The result may be neuronal or white matter injury, or both. Experimental and neuropathological data support this conclusion (see Chapter 19). For example, the neuropathological data reviewed in Chapter 18 suggest a role for hyperoxia in the genesis of a specific pattern of neuronal injury, pontosubicular necrosis, which is most common in the premature infant. In addition, the possibility that hyperoxia may contribute to neuronal injury by causing a reduction in CBF must be considered. Reductions of CBF of 20% to 30% were shown with hyperoxia in newborn puppies, although the arterial oxygen tensions (PaO2) of approximately 350 mm Hg used were very high.512 In one study of 218 term infants with “postasphyxial HIE,” infants who experienced severe hyperoxia (PaO2 > 200 mm Hg) in the first hours of life had an increased risk on multivariate analysis of adverse neurological outcome (OR 3.85; 95% CI, 1.67 to 8.86; P = .002).513 This deleterious effect was accentuated if severe hypocarbia also occurred (see later). A more recent report shows that infants with perinatal acidemia and an initial PaO2 > 100 mm Hg had higher incidences of HIE and of abnormal MRI findings.514 Concern about deleterious effects of hyperoxia has led, in recent years, to a reconsideration of previous recommendations to use 100% oxygen in resuscitation.515-520 Resuscitation with room air versus 100% oxygen has been associated with reduced neonatal mortality. Resuscitation with 100% oxygen also appears to increase oxidative stress.521 A recent meta-analysis compared 100% oxygen resuscitation to room air resuscitation of depressed term newborn infants.522 The data showed a lower mortality both in the first week of life (OR 0.70; 95% CI, 0.50 to 0.98) and at 1 month and beyond (OR 0.63; 95% CI, 0.42 to 0.94) in the room air resuscitation group. Importantly, the incidence of severe HIE (stage II and stage III) was similar between the two groups. Whether the higher levels of oxygen administered contribute to increased oxidative stress in brain, deleterious for both neurons and differentiating oligodendrocytes (see Chapters 13, 14, 15, 17, and 18), is not yet known, although experimental data support this possibility (see Chapter 16).523 The International Liaison Committee on Resuscitation (ILCOR) recommendations for neonatal resuscitation in the term-born infant requiring resuscitation include initiation of oxygen with room air or oxygen concentrations between 21% (room air) and 40%, with increasing oxygen to be used if the response is poor.524

Carbon Dioxide Because PaCO2 may have serious metabolic and vascular effects, careful control thereof is critical (Table 20.33). A consistent body of evidence appears to indicate deleterious effects of alterations in PaCO2 on outcomes following cerebral injury.525 These effects may relate to hypocarbia, hypercarbia, or the degree of variability in PaCO2 levels.526 As with oxygen determinations, periodic sampling of arterial blood is not an optimal means to monitor serially and to maintain PaCO2. Experience with continuous

TABLE 20.33 Deleterious Consequences of Disturbed Carbon Dioxide Levels Hypercarbia (marked) Metabolic Cerebral acidosis Vascular Pressure-passive cerebral circulation Cerebral vasodilation with hemorrhagic complications (e.g., hemorrhagic infarction) Intracranial “steal” Hypocarbia Vascular Diminished cerebral blood flow: ischemic injury

transcutaneous monitoring of PCO2 or serial measurements of end-tidal carbon dioxide pressure indicates that frequent clinical events result in marked changes in PaCO2.527-531

Hypercarbia.  Marked elevations of PaCO2 are particularly

dangerous in infants with HIE because of the resulting increase in tissue PCO2 and consequent worsening of intracellular acidosis in brain (see Table 20.33). Perhaps more important than the metabolic effects and worsening of tissue acidosis are the vascular effects of hypercarbia. Thus, hypercarbia results in an impairment of cerebrovascular autoregulation and, as a consequence, a pressure-passive circulation (see Chapter 13). In one careful study of 43 ventilated preterm infants in the first week of life, a progressive loss of vascular autoregulation was observed with PaCO2 values of 45 mm Hg or greater.532 As noted previously, with hypercarbia resulting in potent vasodilatory effects, CBF may increase and may cause a risk of hemorrhage in vulnerable capillary beds (e.g., margins of an infarct and thereby hemorrhagic infarct in the term infant with HIE). Finally, the cerebral vasodilation in uninjured areas may lead to “steal” of blood from those reversibly injured areas in need of maximal substrate supply. (This risk, shown in adult experimental models, has not been studied in a newborn model.)

Hypocarbia.  The effect of hypocarbia on CBF is pronounced.

Although marked diminutions have been documented in adult humans and animals,533-535 the findings in neonatal animals have not been entirely consistent.536-546 Differences in results appear to relate in part to species and methodological differences. The following conclusions seem warranted. With hypocarbia to approximately 20 mm Hg, little change in CBF occurs. With lower levels (mean, 17 mm Hg), a definite decline in regional CBF occurs in the puppy,541 more marked (30% to 60%) in regions with highest basal levels of blood flow and, therefore, highest sensitivity to carbon dioxide (see Chapter 13) (i.e., brain stem and diencephalon). However, in the piglet, extreme hypocarbia (<15 mm Hg) is necessary to produce statistically significant decreases in blood flow, and in this animal, the cerebrum and not the brain stem or diencephalon is affected.540 Perhaps the most consistent observation in the several animal models is that the linear relationship between PaCO2 and CBF becomes curvilinear at tensions lower than 20 to 25 mm Hg533,538,540; the decrease in CBF for a given decrease in PaCO2 becomes considerably less than it is above this lower range of PaCO2. In addition, adaptation occurs such that in

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy the newborn lamb, CBF after 6 hours of PaCO2 of 15 mm Hg is not statistically different from that in control animals.544 Perhaps of greatest importance despite the decreases in CBF in newborn animals, no change in cerebral metabolic rate for oxygen occurs, primarily because of an increase in oxygen extraction.542,544 Thus, mild hypocarbia may be of little or no danger, although data in the human newborn concerning hypocarbia are of concern (see later). Perhaps relevant in this context is the demonstration that mild hypocarbia (PaCO2 of 26 mm Hg) interacted adversely with hypoxic-ischemic insults in the immature rat.547-549 Thus, animals exposed to hypoxia-ischemia during mild hypocarbia sustained a larger decline in CBF, a greater degree of cerebral glucose and energy depletion, and more neuropathological evidence of brain injury than did animals exposed to the same insult but with normocarbia (PaCO2 of 39 mm Hg) or mild hypercarbia (PaCO2 of 54 mm Hg). The latter two groups had better preserved CBF, less severe cerebral biochemical deficits, and less severe brain injury. The mildly hypercarbic animals had the most favorable hemodynamic, biochemical, and neuropathological outcomes. CBF in the human infant is responsive to changes in PaCO2, except under conditions of maximal vasodilation in the mechanically ventilated preterm infant (in the first days of life) and in the asphyxiated term infant.505,532,550-555 Concern for impaired CBF with vasoconstriction caused by hypocarbia seems warranted. One study of 217 term infants with HIE showed, on multivariate analysis, an association between adverse neurological outcome and PaCO2 lower than 20 mm Hg in the first hours of life (OR 2.34; 95% CI, 1.02 to 5.37; P = .04).513 The risk was accentuated (OR 4.56) when severe hyperoxia also was present. The investigators postulated that aggressive early management and resuscitation may be contributory. In the largest study to date of the impact of PaCO2 in infants receiving therapeutic hypothermia, 202 infants in the NICHD randomized controlled trial of systemic therapeutic hypothermia had multiple blood gases recorded prospectively: prerandomization, randomization, 4, 8, and 12 hours of intervention.556 Subsequent blood gases were obtained as per clinical care and were recorded once daily during study intervention. Hypocarbia was common. A total of 181 newborns had at least one PaCO2 concentration below 35 mm Hg, and 100 infants had at least one PaCO2 concentration below 25 mm Hg from birth to 12 hours of intervention (~16.9 hours of age [mean]). Importantly, 95% of these infants were intubated in the delivery room with the median duration of intubation 6 days. Thus, many infants received significant ventilatory support, which has been shown to increase the risk for hypocarbia in the setting of HIE.557 In relation to neurodevelopmental outcome at 18 to 22 months, infants with poor outcome had significantly lower minimum PaCO2 concentrations (median 22 vs. 26 mm Hg), greater fluctuations in PaCO2 concentrations (difference in maximum and minimum PaCO2, SD of PaCO2) and cumulative PCO2 < 35 mm Hg. The study did not find any relationship to hypercarbia exposure but the early period of observation in the first 16 hours of life may have limited the observation of hypercarbia. Thus, hypocarbia and fluctuations in PaCO2, particularly in ventilated infants, are critical to avoid to optimize subsequent neurodevelopmental outcomes in infants with HIE, irrespective of additional neuroprotective approaches.

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TABLE 20.34  Maintenance of Adequate Perfusion Recognition of pressure-passive cerebral circulation Recognition of “normal” arterial blood pressure level Avoidance of systemic hypotension (may cause ischemic injury) Avoidance of systemic hypertension (may cause hemorrhagic complications)

Maintenance of Adequate Perfusion The maintenance of adequate perfusion to brain is a critical aspect of supportive care (Table 20.34). Prevention of additional ischemic injury is important. The basic elements of maintenance of adequate perfusion are summarized in Table 20.34 and in the following discussion.

Recognition of Pressure-Passive Cerebral Circulation As discussed in Chapter 19 (concerning pathogenesis) and Chapter 13, the cerebral circulation of the infant with HIE appears to be pressure passive. This occurrence may relate to a disturbance of autoregulation by complicating hypoxemia or hypercarbia, or both; a postasphyxial impairment of vascular reactivity as observed in experimental models of perinatal asphyxia; an “immature” autoregulatory system with blunted capacity for reactivity because of the deficient arterial muscularis of penetrating cerebral vessels in the third trimester; an intact or partially intact autoregulatory mechanism but with “normal” neonatal blood pressure dangerously close to the downslope of the autoregulatory curve; or a combination of these factors (see Chapters 13 and 18). The important point is that the physician must be aware of the pressure-passive state, must monitor blood pressure continuously and diligently, and must maintain blood pressure at adequate levels to avoid cerebral ischemia or overperfusion. Studies of CBF in human infants with xenon-clearance techniques have documented a pressure-passive state of the cerebral circulation in seriously asphyxiated term infants (see Chapter 13 and earlier discussion).

Recognition of Normal Arterial Blood Pressure Levels in the Newborn A series of studies has investigated normal values for arterial blood pressure in the newborn.558-574 In the largest, most recent series of 406 healthy term-born infants, day 1 median (5th percentile) values for systolic, diastolic, and mean arterial pressure were 65 mm Hg (55 mm Hg), 45 mm Hg (30 mm Hg), and 48 mm Hg (40 mm Hg), respectively. On day 4, these values had increased to 70 mm Hg, 46 mm Hg, and 54 mm Hg, respectively. In clinical practice, we aim to maintain mean arterial blood pressure (monitored by arterial catheter) at greater than 45 mm Hg and to avoid systolic blood pressures greater than 75 mm Hg, principally by maintaining adequate comfort measures, including sedation.

Avoidance of Systemic Hypotension In view of the aforementioned considerations concerning a pressure-passive cerebral circulation and neonatal blood pressure data, it is clear that systemic hypotension must be avoided because of the danger of cerebral hypoperfusion (see Table 20.34). Moreover, because “normal” arterial blood pressure values in the newborn are relatively low and may be dangerously

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Adrenal insufficiency

Hypothermia

Myocardial ischemia

Pulmonary hypertension

↓ Contractility

↓ LV preload

↓ Vascular tone and inotrope resistance

CNS redistribution

↓ HR

Rewarming

↑ HR

Loss of cerebral autoregulation

↓ PVR and ↑ PBF

↑ Stroke volume

Rapid ↑ in cerebral blood flow

↓ Cardiac output

Ischemic injury

↑ Cerebral metabolism

Oxidative free radical production

Reperfusion injury Abnormal outcome Etiology of physiological change Hypoxic-ischemic insult Therapeutic hypothermia Rewarming

Figure 20.30  Interrelationship between contributors to ischemic injury resulting from initial insult, TH, and reperfusion injury on rewarming. Both ischemia and reperfusion injury may contribute to the degree of brain injury via modification of cardiovascular factors. Resumption of cellular activity after transient suppression is a putative source of potentially damaging oxidative radicals. HR, Heart rate; LV, left ventricle; PBF, pulmonary blood flow; PVR, pulmonary vascular resistance; RV, right ventricle. (From Giesinger RE, Bailey LJ, Deshpande P, McNamara PJ. Hypoxic–ischemic encephalopathy and therapeutic hypothermia: the hemodynamic perspective. J Pediatr. 2017;180:22–30.)

close to the downslope of even an intact autoregulatory curve, the margin of safety for arterial blood pressure sufficient to maintain adequate cerebral perfusion is likely to be small. As noted in Chapter 13 concerning pathogenesis, brain regions that are particularly vulnerable include neuronal-rich areas (cerebral cortex, basal ganglia, thalamus) and regions with vascular border zones and end zones (the parasagittal cerebral areas in the term newborn and to a lesser extent, the periventricular white matter). The principal causes of serious systemic hypotension in the asphyxiated infant are cardiogenic. Evidence of ischemia to papillary muscle, subendocardial region, and myocardium more diffusely has been demonstrated in asphyxiated infants.575-583 In a study of 20 asphyxiated term infants, 8 exhibited myocardial dysfunction in the first 2 postnatal days, and this dysfunction was associated with both reduced cardiac output and lower mean CBF velocity than observed on recovery at 3 days.583 With the introduction of therapeutic hypothermia as standard of care in the infant with moderate-severe HIE, cardiovascular evaluation and management has become more challenging. The impact of therapeutic hypothermia on the cardiovascular system has been extensively reviewed recently and is outlined in Fig. 20.30.584 The evaluation of the cardiovascular system is more challenging in the infant receiving therapeutic hypothermia, due to bradycardia with resulting decreased cardiac output,

peripheral vasoconstriction with hypothermia, and persisting lactic acidemia from the initial ischemic insult. Thus, targeted echocardiography has been recommended to better define the nature of contributing cardiovascular factors, such as cardiac output, superior vena caval flow, and pulmonary hypertension (see review).584 The relative roles of volume expansion, dopamine, dobutamine, phosphodiesterase III inhibitors (e.g., milrinone), and corticosteroids are currently under active study and relate in part to the underlying pathophysiology (as outlined in Fig. 20.30).585-590 Detailed discussion is beyond the scope of this book.

Avoidance of Systemic Hypertension The other side of the coin regarding the issue of cerebral ischemia just discussed is cerebral overperfusion. Because of a pressure-passive cerebral circulation, increases in systemic blood pressure, especially abrupt increases, could lead to rupture of certain vulnerable capillaries and thereby to hemorrhagic complications (see Table 20.34; Fig. 20.30). The causes of such elevations in blood pressure can range from apparently innocuous events, such as simple handling of the infant, to more obvious events, such as overly exuberant administration of volume expanders or pressor agents, seizures, pneumothorax, or abrupt closure of patent ductus arteriosus. Concern for the role of cerebral overperfusion is prominent in the era

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy of therapeutic hypothermia. In one study of a series of 24 term-born infants receiving therapeutic hypothermia, normal brain MRI was associated with lower cerebral blood flow, which further declined in those undergoing hypothermia therapy, compared with infants with poor radiologic outcome who had a higher baseline and a progressive rise in cerebral blood flow despite therapeutic hypothermia.591 Because cerebral hyperfusion may occur following cerebral injury (see Chapter 13), the apparent hyperperfusion in the infants with abnormal MRI may reflect a consequence rather than a cause of injury. More data are needed to resolve this issue. One of the vulnerable periods for cerebral overperfusion in the term infant receiving therapeutic hypothermia is the period of rewarming, which occurs 72 hours after hypothermia has been commenced. In the full-term infant, vulnerable capillaries include those at the margins of cerebral infarcts or in residual germinal matrix, and thus hemorrhagic infarction or intraventricular hemorrhage may occur. In a cohort of 160 asphyxiated neonates, of whom 9% developed intraventricular hemorrhage, hemorrhage at the time of rewarming was associated with a greater degree of hemodynamic instability.592 The essential point is that arterial blood pressure must be monitored carefully, and events that lead to abrupt increases in arterial blood pressure must be prevented or corrected promptly.

Maintenance of Adequate Glucose Levels The roles for endogenous glucose stores, particularly at the time of the asphyxial insult, and for the addition of exogenous glucose after the insult, remain to be established clearly for the human infant. In Chapter 13, the available information based on experiments in immature and mature animals was reviewed. The former experiments suggest, although not uniformly, a generally beneficial effect of glucose, and the latter experiments suggest a deleterious effect. These experiments are relevant particularly to the treatment of the asphyxiated human fetus and, thus, the management of labor and delivery, detailed consideration of which is not within the province of this book. The precise role of glucose in the management of the infant who already has experienced an asphyxial insult needs to be defined further. As described in detail in Chapter 13, studies in perinatal models of hypoxic-ischemic insults indicate that the effects of glucose administration vary considerably, perhaps because of species and other methodological differences. Neuropathological injury has been reported to be prevented, ameliorated, or accentuated in different models. Improved survival with glucose administration is generally consistent and may relate at least partially to improvement in cardiorespiratory function. In human studies, intrapartum hypoxia-ischemia disturbs the typical metabolic transition and increases the likelihood of low blood glucose concentrations through several mechanisms. There is prolonged duration of anaerobic glycolysis, leading to a rapid depletion of glycogen stores. Infants with HIE have significantly lower blood glucose concentrations in the delivery room (before intravenous glucose has been given) than do matched healthy infants (1.95 [SD 0.63 mmol/L] vs. 3.16 [SD 0.31 mmol/L]).593 In addition to depleted stores, the infant with HIE may have increased peripheral glucose utilization, which can be compounded by transient hyperinsulinism,594 and impaired counter-regulatory hormone and enzyme responses. These factors may account for the high prevalence (25%) of infants with moderate to severe HIE with blood glucose values

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of less than 2.6 mmol/L, as reported to the UK TOBY cooling register.595 Several clinical observational studies have suggested a potentiating impact of hypoglycemia on cerebral injury in the infant with HIE. One report involved 185 term-born infants with acidemia (pH < 7.0) admitted to a NICU, and found that those with an initial blood glucose concentration of 2.22 mmol/L (45 mg/dL) or less were at a higher risk of abnormal neurological outcome than infants whose first blood glucose measurement was more than 2.22 mmol/L (56% vs. 16%). In a multivariate logistic analysis that included severity of acidosis and other measures of illness severity at birth, the OR for low blood glucose and poor outcome was 18.5 (95% CI, 3.1 to 111.9).82 In a smaller study of 52 infants with HIE, blood glucose values of less than 2.6 mmol/L, 0 to 6 hours following birth, were associated with poor neurodevelopmental outcome at 24 months, but the association was insignificant after adjustment for severity of HIE.596 These authors concluded that hypoglycemia may be a marker of the duration and severity of the ischemic insult rather than an independent injurious factor. In a more recent study of infants with HIE (defined as umbilical artery pH values of <7.1, umbilical artery base deficits of >10 mmol/L, or 5 minutes Apgar scores of ≤5), the presence of hypoglycemia (any blood glucose concentration <2.6 mmol/L within 24 hours of birth) predicted corticospinal tract injury (OR 3.72; 95% CI, 1.02 to 13.57) and poor neurodevelopmental outcomes at 12 months in multivariate regression analyses that controlled for clinical markers of the degree of hypoxia–ischemia.597 The authors hypothesized that the ischemic cerebral insult may have increased the vulnerability of the brain at levels of blood glucose that are tolerated, in the absence of HIE, by a healthy, breast-fed infant. These conclusions were shared in a recent editorial related to the impact of hypoglycemia on patterns of cerebral injury on MRI in the term-born infant.598 There are insufficient data concerning the blood glucose level that will provide optimal glucose delivery to the brain, as outlined in a recent review of this topic.599 By definition, an infant with moderate to severe HIE displays abnormal neurological signs and should therefore have blood glucose levels maintained above 2.5 mmol/L. However, infants with HIE may require higher concentrations of glucose,600 as suggested by animal data and human studies described earlier. Regarding hyperglycemia, early hyperglycemia (>150 mg/ dL, >8.3 mmol/L) has been associated with greater risk of neurodevelopmental disability (adjusted OR 6.2 and 2.7, respectively) 18 months in term infants with HIE.601,602 In a further secondary analysis of the NICHD Cool Cap study of 194 term-born infants with HIE, in the first 12 hours, 9% (18/194) of infants had ≥1 episode of hypoglycemia, 45% (87/194) had ≥1 episode of hyperglycemia, and 46% (89/194) were normoglycemic.603,604 In this study, in the hyperglycemic infants it was apparent that hypothermia therapy conferred a lower risk of adverse outcome (adjusted risk ratio [aRR] 0.80; 95% CI, 0.66 to 0.99), whereas there was no reduction in risk of adverse outcome associated with hypothermia therapy in the normoglycemic (aRR 0.95; 95% CI, 0.70 to 1.27) or hypoglycemic infants (aRR 1.03; 95% CI, 0.52 to 2.00). A further small study examined the extent by which glucose variability influenced outcomes in term-born infants with hypoxic-ischemic injury. The neurodevelopmental outcomes from 8 of 23 patients were considered severe, and this group demonstrated a significant increase of mean absolute glucose

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TABLE 20.35 Maintenance of Adequate Blood Glucose Levels Maintain a blood glucose concentration of approximately 50–100 mg/dL Avoid hypoglycemia because it may cause neuronal injury Avoid marked hyperglycemia because it may provoke hemorrhage (through a hyperosmolar effect) or may worsen cerebral lactic acidosis

change from birth (95% CI, −0.28 to −0.03; RR = 0.1; P = 0.03). There were no differences between outcome groups with regard to the number of patients with hyperglycemia (mean), and/or one or multiple hypo- or hyperglycemic measurement(s). There were also no differences between groups for mean glucose.603 Given the evidence presented, it has been postulated that glucose may be a marker of the timing and severity of brain injury. Thus, hypoglycemia may be a marker of a more severe and prolonged hypoxic-ischemic insult, compared with hyperglycemia, which may represent an acute insult. The latter may demonstrate greater benefit from hypothermia therapy. In addition, major fluxes in blood glucose also may be injurious. Thus, in collaboration with guidelines from broader arenas of knowledge/research/academic discovery, we currently recommend that glucose supplementation be adjusted to maintain a blood glucose level between approximately 50 and 100 mg/dL (Table 20.35) and that fluxes be minimized.

Control of Seizures Therapy for seizures begins with careful serial observations to detect clinical seizure activity (see Chapter 12). Seizures, an accompaniment of the majority of cases of serious HIE, may cause further injury to the brain. For example, in one detailed study of 90 term infants with perinatal asphyxia, each increase in seizure severity score was independently associated with an increase in lactate and a decrease in NAA, which was assessed by MR spectroscopy (see Chapter 12)335 Later clinical studies support the conclusion that greater frequency and severity of seizures in infants with HIE are associated with a greater degree of brain injury and poorer neurodevelopmental outcome.605-609 Seizures are associated with a markedly accelerated cerebral metabolic rate, and if, as indicated earlier, cerebral metabolism is not operating at optimal aerobic capacity (e.g., because of mitochondrial injury), this acceleration may lead to a rapid fall in brain glucose, an increase in lactate, and a decrease in high-energy phosphate compounds. Moreover, the excessive synaptic release of certain excitotoxic amino acids (e.g., glutamate) also may lead to cellular injury. In addition, seizures are associated frequently with hypoventilation and apnea with consequent hypoxemia and hypercarbia, the dangers of which have been discussed. Studies with transcutaneous tissue electrodes suggest that these latter changes may occur with seizures that are so subtle that they are readily missed clinically. In addition, neonatal seizures are associated with abrupt elevations in arterial blood pressure (see Chapter 12), and hence the possibility of inducing hemorrhage, as discussed earlier. Moreover, studies of ischemia in the term fetal lamb indicate that epileptiform activity is a prominent feature in the hours following the insult (maximum at 10 hours, duration

of 72 hours) and that cortical neuronal necrosis occurs in the same cortical areas and to a degree that correlates with the extent of epileptiform activity.610 Moreover, infants with poorly controlled seizures have more frequent and severe neurological sequelae than infants whose seizures are well controlled.20,335,611,612 Obviously, this difference may relate to the severity of the initial injury rather than to additional injury from repetitive seizures. Indeed, studies in neonatal rats subjected to hypoxia-ischemia and subsequent chemically induced seizures at 2, 6, and 12 hours of recovery showed no accentuation of brain damage compared with histopathological findings in rats subjected to hypoxia–ischemia without induced seizures.613-615 However, the convulsing animals developed hypoglycemia and a mortality rate of 53%, both of which could be improved by glucose supplementation.613 Nevertheless, on balance, the data do raise the possibility of a deleterious effect of multiple seizures in the infant with HIE. Careful attention to glucose homeostasis clearly is critical in this context. Phenobarbital remains the preferred drug for the treatment of seizures in neonatal HIE; details of the administration of this drug are described in Chapter 12. The timing of treatment has been somewhat controversial. Pretreatment with barbiturates (i.e., before the onset of seizures) has been considered because of studies in adult animals that barbiturates in high doses are beneficial in ischemia (by causing reduction of cerebral metabolic rate, cerebral vasoconstriction, reduction of brain edema, or removal of harmful free radicals)616-621 and studies in perinatal animals that suggest a beneficial effect in several nonprimate species and in term fetal monkeys.549,622-629 In the study of the fetal monkey by Cockburn and co-workers,628 anesthetic doses of pentobarbital that were administered to the mothers produced anesthesia in the fetuses, which were then delivered and asphyxiated experimentally. When compared with animals delivered under local anesthesia before asphyxia, the barbiturate-treated animals had prolongation of time to last gasp, accelerated establishment of rhythmic breathing after resuscitation, and less histological evidence of neuronal injury. In the only study of neonatal monkeys treated with barbiturates after birth but before asphyxia, no beneficial effect on time to last gasp, survival, or CBF could be detected.630 In this study, a 20-mg/kg dose of phenobarbital was administered in the 18 hours before asphyxia, and animals were sedated but not anesthetized, a potentially important difference from the study of Cockburn and co-workers.628 No experimental studies have been reported in which barbiturates have been administered after a perinatal asphyxial insult. Studies of pretreatment of asphyxiated term infants with barbiturates (i.e., before the occurrence of seizures) have shown interesting but not entirely consistent results.631,632 In one randomized, controlled trial of 32 severely asphyxiated term infants, thiopental was administered initially at a mean age of 2.3 hours and then by constant infusion over 24 hours.632 Seizures occurred in approximately 75% of both treated and control infants. Moreover, the mortality rate and neurological outcome were similar in the two groups. Of concern is that hypotension occurred in nearly 90% of the treated group and required pressor agents in 30%. An earlier study, which used a slightly smaller number of severely asphyxiated infants, suggested benefit for relatively high doses of phenobarbital administered shortly after birth.633 A total of 14 infants were treated within 60 minutes of delivery

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy with phenobarbital (10 mg/kg, followed in 4 hours by 10 mg/ kg per day), in addition to assisted ventilation, glucocorticoid, and fresh frozen plasma. (Another group of 16 infants did not receive glucocorticoid or fresh frozen plasma therapy and were given phenobarbital only if seizures did not respond to diazepam.) Plasma levels of phenobarbital in the early-treated infants were approximately 25 µg/mL on the first day and rose to a peak of 40 to 70 µg/mL on the second and third days. Respiratory “insufficiency” was noted at levels higher than approximately 40 µg/mL, and phenobarbital administration “may have prolonged ventilator treatment in some infants.”633 When compared with infants not treated early with phenobarbital, the early phenobarbital-treated infants had lower mortality rates (14% vs. 50%) and a more frequent normal outcome in survivors (83% vs. 50%). Obviously, the numbers are small, the groups were not comparably treated with respect to factors other than phenobarbital, and the side effects are disturbing. A later study evaluated the effect of administration of 40 mg/ kg of phenobarbital to term infants with “severe asphyxia” (initial arterial pH ≤ 7.0 and base deficit of 15 mEq/L or more, Apgar score ≤3 at 5 minutes of age, or failure to initiate spontaneous respirations by 10 minutes of age) at a mean age of 6 hours and before the onset of clinical seizures.634 Seizures occurred in 9 of 15 treated infants versus 14 of 16 “control” infants (P = .11). At 3 years of age, normal outcome was noted in 11 of 15 treated infants versus only 3 of 16 control infants (P = .003). Thus, although early onset of high-dose phenobarbital therapy was not associated with a statistically significant reduction in the occurrence of seizures, a beneficial effect on neurological outcome was suggested. The potential value of prophylactic phenobarbital (40 mg/kg given at the time of onset of cooling) was studied in 42 infants with HIE.635 A decrease in the frequency of neurodevelopmental impairment in the prophylactic phenobarbital group (23%) versus the nonprophylactic group (45%) was not statistically significant. There were fewer clinical seizures in the prophylactic group than in the cooled infants not given prophylactic phenobarbital (15% vs. 82%; P < .0001). More data will be of interest. Currently, we do not administer phenobarbital routinely before the onset of clinical or electrographic seizures. However, we use the EEG tracing to identify seizures and to provoke prompt treatment. Phenobarbital sometimes is not optimally effective in the severely asphyxiated infant. This situation results most probably because (1) phenobarbital is a gamma-aminobutyric acid (GABA) agonist; (2) GABA receptors tend to be excitatory in the newborn brain because of high intracellular chloride levels; and (3) the expression of the NKCC1 transporter for chloride influx is activated after hypoxia-ischemia (see Chapter 12).636 However, trials of newer additive agents, such as bumetanide, a diuretic and inhibitor of NKCC1, and levetiracetam, are currently underway. The largest published study to date is an open-label, dose finding, and feasibility phase 1/2 trial, with recruitment of full-term infants less than 48 hours of age with HIE and electrographic seizures not responding to a loading dose of phenobarbital (NCT01434225). The authors reported on 14 infants (10 males) with bumetanide dose allocation: 0.05 mg/kg, n = 4; 0.1 mg/ kg, n = 3; 0.2 mg/kg, n = 6; 0.3 mg/kg, n = 1.637 All infants received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated

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to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (1 on 0.05 mg/kg, 1 on 0.1 mg/kg and 3 on 0.2 mg/kg), and only 2 of the 14 did not need rescue antiepileptic drugs (i.e., met rescue criteria; 1 on 0.05 mg/kg and 1 on 0.3 mg/kg). Three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common nonserious adverse reactions were moderate dehydration in 1, mild hypotension in 7, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction. The authors concluded that bumetanide as an add-on to phenobarbital did not improve seizure control in newborn infants who have HIE, and might increase the risk of hearing loss, which highlighted the risks associated with the off-label use of drugs in newborn infants. A further randomized, controlled trial (NCT00830531) is currently being undertaken in the United States with phenobarbital combined with either 0.1 mg/kg, 0.2 mg/kg, or 0.3 mg/kg of bumetanide as determined by the status of the dose escalation design. Topiramate, an anticonvulsant agent, which potentiates the neuroprotective effect of hypothermia (see later and Chapter 13), is also a candidate for further study in the context of HIE. Further data are required before implementation of these agents as standard clinical practice.

Neuroprotective Interventions As described in detail in Chapters 13 and 19, the principal mechanisms of neuronal death in HIE operate after termination of the insult, are initiated by the activation of glutamate receptors, occur over hours, and involve the accumulation of cytosolic calcium and the activation of a variety of calcium-mediated deleterious events, including especially the generation of free radicals, such as superoxide anion, hydroxyl radical, and nitric oxide derivatives. Free radical-mediated cell death also appears to be the final common pathway for cell death (see Chapters 13 and 19). The exciting implication concerning management is that interruption of this deleterious cascade, even after termination of the insult, could prevent or ameliorate the brain injury in perinatal hypoxic-ischemic disease. In Chapter 13, potential neuroprotective interventions shown to be of value in a variety of experimental models of hypoxia-ischemia are discussed. In this section, we discuss primarily those agents studied in human newborns (Table 20.36). The approaches that have been studied in human infants and considered here are therapeutic hypothermia, anticonvulsant therapy, xenon, antioxidants, melatonin, erythropoietin, magnesium, calcium channel blockers, and stem cell transplantation (see Table 20.36). Several other promising pharmacologic agents, still in a preclinical stage, are also noted briefly.

Hypothermia Although for many decades, deep hypothermia to body temperatures less than 20°C has been shown to be valuable for neuroprotection during cardiac surgery with circulatory bypass or circulatory arrest, in recent years, after numerous experimental studies in a variety of models of perinatal hypoxia-ischemia, it has shown a pronounced beneficial effect with induced hypothermia of only a few degrees (i.e., “mild”

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hypothermia; see Chapter 13) has been shown. This approach has been studied in human infants with HIE and is now adopted worldwide. The principal determinants of neuroprotective benefit for mild hypothermia have related to timing (onset of hypothermia before delayed energy failure and excitatory features, such as seizures [i.e., ≈6 hours]), degree (decrease of body temperature by 3°C to 4°C), and duration (≈72 hours). The mechanisms of benefit appear to include a decrease in energy consumption, a decrease in the accumulation of extracellular glutamate, a decrease in the generation of reactive oxygen and nitrogen species, inhibition of inflammatory mechanisms, and the interruption of downstream molecular cascades to apoptosis (see Chapter 13). On the background of the promising results of mild hypothermia in experimental models, multicenter, randomized, clinical trials in term infants with HIE were initiated with consistent findings of benefit.71,476,601,638-655 Two principal approaches have been used: selective head cooling (by a water-circulating cap, “Cool Cap”) or whole body cooling (by water-circulating blankets) (Fig. 20.31). The first large-scale multicenter study reported involved selective head cooling.601 In this landmark study, 218 infants with moderate to severe encephalopathy and abnormal aEEG were randomized

TABLE 20.36 Neuroprotective Interventions in the Human Fetus and Newborna Mild hypothermia Anticonvulsant drugs Xenon Antioxidants—N-Acetylcysteine, allopurinol Melatonin Erythropoietin Magnesium Calcium channel blockers Stem cell transplantation Other pharmacologic agents a

See text for details.

A

to cooling therapy that began before 5.5 hours of age and continued for 72 hours. In a minority of infants (n = 46) who had severe aEEG abnormalities, no effect on death or severe disability at 18 months was observed. However, in a majority of infants who had moderate aEEG abnormalities (n = 172), a significantly lower rate of this unfavorable outcome was observed in the hypothermic group versus the control group (48% vs. 66%, P = .02). Similarly, early promising results were obtained from the multicenter trial of whole body cooling.71 The total group included 208 infants with moderate or severe encephalopathy; aEEG was not used in this study. Cooling was begun at a mean age of 4.3 hours to an esophageal temperature of 33.5°C and was continued for 72 hours. Death or moderate or severe disability occurred in 44% of the hypothermic infants versus 62% of the control infants (P = .01). In the most recent meta-analysis of 11 randomized controlled trials of 1505 term and late preterm infants with moderate/ severe encephalopathy and evidence of intrapartum asphyxia,510 therapeutic hypothermia resulted in a significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.75 [95% CI, 0.68 to 0.83]; typical risk differences [RD] −0.15, [95% CI, −0.20 to −0.10]); number needed to treat for an additional beneficial outcome (NNTB) 7 (95% CI, 5 to 10) (8 studies, 1344 infants) (Fig. 20.32). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 [95% CI, 0.64 to 0.88]; typical RD −0.09 [95% CI, −0.13 to −0.04]); NNTB 11 (95% CI, 8 to 25 [11 studies, 1468 infants]) and in neurodevelopmental disability in survivors (typical RR 0.77 [95% CI, 0.63 to 0.94]; typical RD −0.13 [95% CI, −0.19 to −0.07]); NNTB 8 (95% CI, 5 to 14; [8 studies, 917 infants]). The selection of infants that may benefit from hypothermia therapy has been investigated and the following indications for the initiation of hypothermia endorsed by the American Academy of Pediatrics207: 1. More than 35 weeks gestational age 2. Less than 6 hours of age 3. “Evidence of asphyxia,” as defined by the presence of at least 1 to 2 of the following:

B Figure 20.31  Two approaches to hypothermia. (A) Selective head cooling with head wrap and chin straps. (B) Infant receiving whole body therapeutic hypothermia via body wrap.

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy Hypothermia Standard care Study or subgroup Events Total Events Total 1.1.1 Selective head cooling with mild systemic hypothermia Gunn 1998 Cool Cap Study 2005 Zhou 2010 Subtotal (95% Cl)

7 59 31

18 108 100 226

4 73 46

Risk ratio Weight M-H, Fixed, 95% Cl

13 110 94 217

1.1% 17.6% 11.5% 30.3%

1.26 [0.46, 3.44] 0.82 [0.66, 1.02] 0.63 [0.44, 0.91] 0.77 [0.64, 0.92]

25 103 162 58 101 449

5.3% 15.5% 21.0% 11.2% 16.8% 69.7%

0.62 [0.41, 0.92] 0.71 [0.54, 0.93] 0.86 [0.68, 1.07] 0.62 [0.46, 0.82] 0.77 [0.62, 0.98] 0.75 [0.66, 0.84]

666

100.0%

0.75 [0.68, 0.83]

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Risk ratio M-H, Fixed, 95% Cl

Total events 97 123 Heterogeneity: Chi2 = 2.46, df = 2 (P = 0.29); I2 = 19% Test for overall effect: Z = 2.78 (P = 0.005) 1.1.2 Whole body cooling Eicher 2005 NICHD Study 2005 TOBY Study 2009 neo.nEURO Study 2010 ICE Study 2011 Subtotal (95% Cl)

14 45 74 27 55

27 102 163 53 107 452

21 64 86 48 67

215 286 Total events Heterogeneity: Chi2 = 4.25, df = 4 (P = 0.37); I2 = 6% Test for overall effect: Z = 4.80 (P < 0.00001) 678

Total (95% Cl) 312

Total events

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A Outcome

Number of studies/number of participants

Mortality ND disability in survivors Severe cerebral palsy MDI <70 PDI <70 Severe visual deficit Severe hearing deficit Epilepsy Life support withdrawn

12 / 1390 6 / 687 3 / 518 4 / 522 4 / 512 4 / 535 4 / 510 5 / 413 6 / 746

Relative risk

Relative risk

0.78 (0.65, 0.92) 0.67 (0.54, 0.84) 0.65 (0.48, 0.88) 0.70 (0.54, 0.90) 0.70 (0.54, 0.90) 0.59 (0.35, 0.98) 0.75 (0.36, 1.55) 0.80 (0.48, 1.31) 0.93 (0.73, 1.18) 0.5

B

Hypothermia

1

1.5 Normothermia

Figure 20.32  Therapeutic hypothermia outcomes. (A) Primary outcomes in randomized controlled trials of therapeutic hypothermia. (B) Outcomes from therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy.

• Apgar score less than 6 at 10 minutes or continued need for resuscitation with positive pressure ventilation or chest compressions at 10 minutes • Any acute perinatal sentinel event that may result in HIE (e.g., abruptio placentae, cord prolapse, severe FHR abnormality) • Cord pH < 7.0 or base excess of −16 mmol/L or less • If cord pH is not available, arterial pH < 7.0 or base excess less than −16 mmol/L within 60 minutes of birth 4. Presence of moderate/severe neonatal encephalopathy on clinical examination The issue of initiation of therapeutic hypothermia in mildly encephalopathic infants is currently under active investigation. Although infants with milder degrees of clinical encephalopathy were not eligible in any of the RCTs, a small number of mildly

encephalopathic infants were enrolled in two trials (total n = 79).651,656 This inclusion of milder cases may reflect the difficulty of firmly assigning the severity of NE within the first hours of life and is consistent with the common clinical situation.595,657,658 Zhou et al. randomized 39 infants with mild NE, 21 to treatment with hypothermia, and 18 controls.656 No infant with mild NE met the primary outcome of death or severe disability. However, 33% (13/39) of those with mild NE were found to have a moderately abnormal outcome (a developmental quotient between one to two standard deviations below the mean at 18 months of age, with the Gesell Child Development Age Scale). Stratification by treatment group showed that 29% (6/21) who received hypothermia versus 39% (7/18) of control infants had a moderately abnormal outcome (P = 0.3). In the ICE trial, Jacobs et al. randomized 40 infants with mild neonatal

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encephalopathy, 16 to treatment with hypothermia, and 24 controls.651 A total of 30% (12/40) of infants with mild NE met the composite primary outcome of death or severe disability at 2 years of age. Severe disability was defined as any one of: cerebral palsy, a Psychomotor Development Index score on the Bayley-II of greater than two standard deviations below the mean, a Motor Composite Scale score on the Bayley-III of greater than two standard deviations below the mean, or a disability level on the Gross Motor Function Classification System of two to five. Stratification by treatment group showed that 25% (4/16) who received therapeutic hypothermia versus 33% (8/24) of control infants met the primary outcome (RR 0.53; 95% CI, 0.17 to 1.66). Thus, both of these demonstrated a trend toward improved outcome among the hypothermia group, with an RR reduction with hypothermia treatment of 26% in the study of Zhou et al., and 24% in the ICE trial. These reductions in the risk of adverse outcomes are similar to those reported for death or disability for therapeutic hypothermia in the setting of moderate–severe neonatal encephalopathy, but are very underpowered for definition. Finally, it is noteworthy that the rates of adverse outcome for infants with mild NE after therapeutic hypothermia reported in both trials are almost identical to the frequency of moderate-severely abnormal MRIs (23%) among infants with mild NE reported in other studies.658-660 Thus, the inclusion of such infants with mild disease for treatment in clinical practice continues to expand without any randomized trial.595,657,658 Further data are needed on the efficacy of this neuroprotective therapy in this group.656 Thus, to conclude, it is clear from available clinical and preclinical evidence that moderate therapeutic hypothermia should be implemented as soon as possible, before the onset of secondary injury and continued until this period of secondary energy failure has resolved.661 Infants cooled within 3 hours of birth appear to have better neurodevelopmental outcomes compared with infants whose cooling commences between 3 hours and 6 hours.662 Following 72 hours of cooling, infants should be slowly rewarmed (0.5°/hour). This rate is based on animal data showing increased seizures663 and increased cortical apoptosis with664 rapid rewarming. Longer periods of cooling (>72 hours) or deeper cooling to less than 33.5°C has not been shown to be of benefit, and is harmful.665-668 The risk factors associated with therapeutic hypothermia appear to be relatively minor compared to the potential benefit from the therapy.510 To conclude, it is now clear that early implementation of therapeutic hypothermia to at-risk infants for HIE reduces the extent of cerebral injury on MRI, reduces mortality, and improves neurodevelopmental outcomes. Further research is required to determine the extent to which mild HIE is an indication for the implementation of this approach.

Other Neuroprotective Agents As discussed in Chapter 13, experimental studies suggest that some neuroprotective agents appear to have synergistic or, at least, strong additive effects with hypothermia in models of neonatal hypoxia–ischemia. The principal agents studied have been anticonvulsant drugs, including phenobarbital, topiramate, and levetiracetam; xenon, antioxidants, including N-acetylcysteine and allopurinol; and agents with multiple effects, including erythropoietin and IGF-1. Other neuroprotective interventions for neonatal HIE not studied in relation to hypothermia also will be noted briefly later.

Anticonvulsant Drugs Anticonvulsant drugs may play a neuroprotective role in addition to their anticonvulsant action (see Table 20.36). The potential role for phenobarbital administered prophylactically in infants treated with hypothermia was discussed in the section on control of seizures. A potential role for topiramate in this context, discussed in Chapter 13, and for levetiracetam was noted earlier. This potential is based on studies of experimental models of neonatal HIE, in conjunction with hypothermia, particularly by Silverstein and colleagues.669 Topiramate is not available in parenteral form. Levetiracetam is of particular interest because the agent does not cause neuronal apoptosis in the neonatal animal; it is used for treatment of seizures in the human newborn and is available in parenteral form.

Xenon Xenon is a potent anesthetic with a low gas partition coefficient. It crosses the blood-brain barrier easily and leads to rapid induction of anesthesia. Neuroprotective effects of xenon have been demonstrated in combination with hypothermia (see Table 20.36).670,671 Xenon was reported to be safe for use with hypothermia in a phase II randomized study of outcomes after demonstration of similar results as cooling therapy alone.672 An open-label randomized controlled trial of 92 infants (46 assigned to hypothermia alone, and 46 to hypothermia and xenon therapy) showed no significant differences in lactate/NAA ratio in the thalamus or fractional anisotropy in the posterior limb of the internal capsule.673 The investigators concluded that administration of xenon “is unlikely to enhance the neuroprotective effect of cooling after birth asphyxia.”673

Antioxidants—N-Acetylcysteine, Allopurinol Because oxidative stress is an important mechanism of neonatal hypoxic-ischemic brain injury (see Chapters 13 and 19), agents with antioxidant properties might be anticipated to be useful in neuroprotection. Experimental studies of hypoxia-ischemia in the neonatal rat support this possibility.674 N-acetylcysteine in combination with hypothermia was particularly beneficial. Potential value for N-acetylcysteine is supported by its ability to cross the blood-brain barrier and relative safety. Data in human infants treated with hypothermia would be of interest. Allopurinol, a xanthine oxidase inhibitor and free radical scavenger, has neuroprotective properties. Data from one report suggested a beneficial effect of allopurinol therapy on free radical formation (measured by the assay of markers in plasma), cerebral hemodynamics (measured by near-infrared spectroscopy), and electrical brain activity (measured by a cerebral function monitor). Short-term outcome (death, neurological abnormalities at discharge) tended to be more favorable in the treated infants, but the difference did not achieve statistical significance.675 A later study also suggested the benefit for allopurinol in asphyxiated term infants.676 In 2014, a large trial of maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in umbilical cord blood. However, post hoc analysis revealed a potential benefit in the treatment of females (NCT00189007).677 Several underpowered clinical trials suggest modest benefit of allopurinol in neonatal HIE.675,678,679 Whether allopurinol

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy could enhance the benefit of hypothermia is unknown but perhaps worthy of study.

Melatonin Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous indolamine that has shown promising effects in the treatment of HIE. It has antioxidant, antiinflammatory, and antiapoptotic properties.680 Melatonin freely crosses the blood-brain barrier. In an animal model of neonatal asphyxia melatonin has been shown to protect the brain independently681 or in concert with therapeutic hypothermia.682 Aly and colleagues demonstrated in a small pilot study of infants with moderate to severe HIE that the combination of melatonin and therapeutic hypothermia was efficacious in reducing oxidative stress and improved survival with favorable neurodevelopmental outcome at 6 months of age.683 Optimal dose, route, and duration of administration still need to be delineated.

Erythropoietin Erythropoietin (EPO) has been investigated as a neuroprotective strategy for both term and preterm infants. EPO is a glycoprotein shown to be involved in the adaptive response to perinatal hypoxia-ischemia and to exhibit neuroprotective properties.684-686 The principal sequence of adaptive events is the induction by hypoxia of a hypoxia-inducible factor, a transcription factor, that then leads to increased expression of EPO and its receptor in neurons, astrocytes, oligodendroglia, microglia, and endothelial cells. The principal neuroprotective mechanisms involve antiexcitotoxic, antioxidant, antiinflammatory, and antiapoptotic effects (see Chapter 13). Numerous experimental studies of neonatal hypoxia-ischemia have shown reductions in brain injury with administration of EPO.687,688 Neuroprotective effects in animal models have been shown by treatment after as well as before the hypoxic-ischemic insult. Moreover, although EPO is a 34-kDa glycoprotein, it has been beneficial after systemic administration. Two clinical trials in human infants with HIE, before the era of hypothermia treatment, suggested a beneficial effect of EPO treatment (for 5 days or 14 days) on neurological outcome.689,690 The possibility that EPO might have an added or even synergistic neuroprotective effect when combined with hypothermia is suggested in part by the broad spectrum of deleterious mechanisms blunted by these two modalities. Initial studies in experimental models provided inconsistent results.691,692 However, a small phase 1 trial (n = 24) suggested benefit for the addition of EPO to hypothermia for HIE.693 Moreover, a later phase II trial (n = 50) of EPO administered in the first week in combination with hypothermia treatment appeared to result in less MRI brain injury and improved 1 year motor function.694 The potential of more prolonged EPO treatment with a longer dosing interval is suggested by a recent safety trial of darbopoietin, an EPO-derived molecule with an extended circulating half-life.695 Currently there are two active clinical trials (NCT01913340 and NCT01732146) examining EPO in combination with hypothermia in infants with HIE. The “Neonatal Erythropoietin and Therapeutic Hypothermia Outcomes in Newborn Brain Injury” study (NCT01913340) assesses an EPO dose of 1000 U/ kg per dose IV × 5 doses, while the “Efficacy of Erythropoietin to Improve Survival and Neurological Outcome in Hypoxic Ischemic Encephalopathy” study (NCT01732146) evaluates

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intravenous erythropoietin at 1000 to 1500 U/kg per dose three times every 24 hours with the first dose within 12 hours of delivery. The outcomes of these trials are awaited before incorporation of this neuroprotective approach as complementary to therapeutic hypothermia. The possibility should be considered that prolonged EPO therapy could be effective in reparative, restorative mechanisms after the initial hypoxic-ischemic injury. Thus, EPO not only has neuroprotective properties but also promotes neurogenesis, oligodendroglial development and angiogenesis (see Chapters 13 and 16). Prolonged EPO treatment perhaps could be useful for recovery/restoration after neuronal and white matter injury. The availability of an agent like darbopoietin (see earlier) with a prolonged circulatory half-life and longer dosing intervals could be valuable in this context.

Magnesium Magnesium sulfate has been used for many years in obstetrics as a tocolytic agent for preterm labor and as therapy for preeclampsia. The evidence of its effectiveness for the latter purpose is stronger than that for its role as a tocolytic. Although magnesium has been shown to be neuroprotective in some animal models of neonatal HIE, the data are inconsistent.696 Similarly, data are not consistent for a beneficial role for antenatal magnesium in prevention of preterm brain injury. Tagin and colleagues in a recent meta-analysis of all available trial data demonstrated that there is insufficient evidence to determine if magnesium therapy given shortly after birth to newborns with HIE reduces death or moderate-to-severe disability.697 Currently, an ongoing phase III clinical trial (NCT01646619) is assessing whether the addition of magnesium sulfate to therapeutic hypothermia for infants who are asphyxiated at birth provides additional benefit to survival and outcomes compared to cooling alone.

Calcium Channel Blockers Because a central mediator of the cascade to neuronal death is elevated cytosolic calcium, caused in part by enhanced calcium influx, the possibility of a protective effect of calcium channel blockers has been investigated. Experimental studies show some benefit (see Chapter 13). However, a single small study of a calcium channel blocker in the treatment of severely asphyxiated infants indicated that further understanding of the toxicity of these agents is necessary before a beneficial effect can be expected.698 We are unaware of any current studies of the use of calcium channel blockers in asphyxiated human infants.

Stem Cell Therapy A potential role for stem cell therapy for neuroprotection and neurorestoration in neonatal HIE is suggested by recent experimental observations (see Table 20.36). Such a role in the treatment of cerebral white matter injury in premature infants and in term infants with neonatal arterial ischemic stroke is discussed in Chapters 16 and 21. In the context of neonatal HIE the principal agents studied in experimental models have been human cord blood, multipotent stem cells and progenitor cells, and neural stem cells.699 Although results are not entirely consistent, generally beneficial effects have been documented. Cord blood is an excellent source of stem and progenitor cells. Experimental studies show that infusion of human cord blood

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in the first 24 hours after hypoxia–ischemia or at 7 days has led to variable benefit, most often functional.700-704 The benefit likely relates not to the major engraftment of cells but rather to antiapoptotic and antiinflammatory effects and perhaps trophic effects on endogenous cells. The administration of autologous, volume- and red-blood-cell-reduced human cord blood to human infants appears to be safe and feasible699 and has been proposed for use in conjunction with hypothermia treatment. Although multiple issues require resolution (e.g., timing, dose, and duration), this avenue of therapy should be explored in carefully designed, controlled trials. An initial trial by Cotten and co-workers of autologous cord blood infusion in term infants with HIE is underway (NCT00593242).705

Other Pharmacological Agents Experimental studies suggest potential neuroprotective roles in neonatal HIE for a variety of other agents, including caspase inhibitors, IGF-1, cannabinoids, and osteopontin (see Table 20.36).706-712 No trials in human infants are available.

Conclusions The prospective studies of the individual agents and interventions discussed in the preceding sections and those likely to be evaluated in the future based on experimental data are necessary and appropriate. However, it seems likely that combinations of agents, including those that affect different levels of the cascade to cell death described in Chapter 13, will prove optimal. Moreover, such combinations may include sequential administration, beginning intrapartum and continuing postnatally. Approaches that are likely to affect common initiating mechanisms (e.g., cerebrovascular autoregulation, cerebral ischemia), as well as common downstream mechanisms (e.g., excitotoxicity, free radical attack, inflammation, apoptosis, especially at multiple sites), will have particular value because both neuronal and oligodendroglial injury could be ameliorated. Mild hypothermia is now an established approach. Agents that potentiate the effect of hypothermia remain crucial topics for future research. Subsequent to or concomitant with the initial phase of neuroprotection, the institution of neurorestorative therapies (e.g., erythropoietin, human cord blood transplantation) may be critical for reparative and regenerative processes.

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Full references for this chapter can be found on www.expertconsult .com.

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy

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125. Silveira RC, Procianoy RS. Interleukin-6 and tumor necrosis factor-α levels in plasma and cerebrospinal fluid of term newborn infants with hypoxic–ischemic encephalopathy. J Pediatr. 2003;143:625-629. 126. Tekgul H, Yalaz M, Kutukculer N, et al. Value of biochemical markers for outcome in term infants with asphyxia. Pediatr Neurol. 2004;31:326-332. 127. Lv H, Wang Q, Wu S, et al. Neonatal hypoxic ischemic encephalopathy-related biomarkers in serum and cerebrospinal fluid. Clin Chim Acta. 2015;450:282-297. 128. Liu F, McCullough LD. Inflammatory responses in hypoxic ischemic encephalopathy. Acta Pharmacol Sin. 2013;34:11211130. 129. Swanstrom S, Bratteby LE. Hypoxanthine as a test of perinatal hypoxia as compared to lactate, base deficit, and pH. Pediatr Res. 1982;16:156-160. 130. Hoo JJ, Goedde HW. Determination of brain type creatine kinase for diagnosis of perinatal asphyxia—choice of method [letter]. Pediatr Res. 1982;16:806-806. 131. Kumpel B, Wood SM, Anthony PP, et al. Umbilical cord serum creatine kinase BB in the diagnosis of brain damage in the newborn: problems in interpretation. Arch Dis Child. 1983;58: 382-383. 132. Walsh P, Jedeikin R, Ellis G, et al. Assessment of neurologic outcome in asphyxiated term infants by use of serial CK-BB isoenzyme measurement. J Pediatr. 1982;101:988-992. 133. Worley G, Lipman B, Gewolb IH, et al. Creatine kinase brain isoenzyme: relationship of cerebrospinal fluid concentration to the neurologic condition of newborns and cellular localization in the human brain. Pediatrics. 1985;76:15-21. 134. Cuestas RA Jr. Creatine kinase isoenzymes in high-risk infants. Pediatr Res. 1980;14:935-938. 135. Amato M, Gambon R, von Muralt G. Prognostic value of serum creatine kinase brain isoenzyme in term babies with perinatal hypoxic injuries. Helv Paediatr Acta. 1985;40:435-440. 136. Ezitis J, Finnström O, Hedman G, et al. CKBB-enzyme activity in serum in neonates born after vaginal delivery and cesarean section. Neuropediatrics. 1987;18:146-148. 137. Fernéndez F, Verdu A, Quero J, et al. Serum CPK-BB isoenzyme in the assessment of brain damage in asphyctic term infants. Acta Paediatr Scand. 1987;76:914-918. 138. Ruth VJ. Prognostic value of creatine kinase BB-isoenzyme in high risk newborn infants. Arch Dis Child. 1989;64:563-568. 139. den Ouden L, van de Bor M, van Bel F, et al. Serum CK-BB activity in the preterm infant and outcome at two and four years of age. Dev Med Child Neurol. 1990;32:509-514. 140. De Praeter C, Vanhaesebrouck P, Govaert P, et al. Creatine kinase isoenzyme BB concentrations in the cerebrospinal fluid of newborns: relationship to short-term outcome. Pediatrics. 1991;88:1204-1210. 141. Sobajima H, Togari H. Cerebrospinal fluid neuron-specific enolase as the prognostic marker for long term neurological sequela in the asphyxiated infants—a multicenter prospective study. Nagoya Med J. 1993;37:169-178. 142. Blennow M, Hagberg H, Rosengren L. Glial fibrillary acidic protein in the cerebrospinal fluid: a possible indicator of prognosis in full-term asphyxiated newborn infants? Pediatr Res. 1995;37:260264. 143. Blennow M, Rosengren L, Jonsson S, et al. Glial fibrillary acidic protein is increased in the cerebrospinal fluid of preterm infants with abnormal neurological findings. Acta Paediatr. 1996;85:485-489. 144. Thornberg E, Thiringer K, Hagberg H, et al. Neuron specific enolase in asphyxiated newborns: association with encephalopathy and cerebral function monitor trace. Arch Dis Child. 1995;72:F39-F42. 145. Talvik T, Haldre S, Soot A, et al. Creatine kinase isoenzyme BB concentrations in cerebrospinal fluid in asphyxiated preterm neonates. Acta Paediatr. 1995;84:1183-1187. 146. Blennow M, Savman K, Ilves P, et al. Brain-specific proteins in the cerebrospinal fluid of severely asphyxiated newborn infants. Acta Paediatr. 2001;90:1171-1175. 147. Ezgu FS, Atalay Y, Gucuyener K, et al. Neuron-specific enolase levels and neuroimaging in asphyxiated term newborns. J Child Neurol. 2002;17:824-829.

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219. Medlock MD, Hanigan WC, Cruse RP. Dissociation of cerebral blood flow, glucose metabolism, and electrical activity in pediatric brain death—case report. J Neurosurg. 1993;79:752-755. 220. Okamoto K, Sugimoto T. Return of spontaneous respiration in an infant who fulfilled current criteria to determine brain death. Pediatrics. 1995;96:518-520. 221. Fishman MA. Validity of brain death criteria in infants. Pediatrics. 1995;96:513-515. 222. Shewmon DA, Holmes GL, Byrne PA. Consciousness in congenitally decorticate children: developmental vegetative state as self-fulfilling prophecy. Dev Med Child Neurol. 1999;41: 364-374. 223. Ashwal S, Schneider S. Failure of electroencephalography to diagnose brain death in comatose children. Ann Neurol. 1979;6: 512-517. 224. American Academy of Pediatrics Task Force on Brain Death in Children. Report of special Task Force. Guidelines for the determination of brain death in children. Pediatrics. 1987;80: 298-300. 225. Barnette AR, Horbar JD, Soll RF, et al. Neuroimaging in the evaluation of neonatal encephalopathy. Pediatrics. 2014;133:e1508-e1517. 226. Rutherford MA, Pennock JM, Dubowitz L. Cranial ultrasound and magnetic resonance imaging in hypoxic-ischaemic encephalopathy: a comparison with outcome. Dev Med Child Neurol. 1994;36:813-825. 227. Eken P, Toet MC, Groenendaal F, et al. Predictive value of early neuroimaging, pulsed Doppler and neurophysiology in full term infants with hypoxic-ischaemic encephalopathy. Arch Dis Child. 1995;73:F75-F80. 228. Daneman A, Epelman M, Blaser S, et al. Imaging of the brain in full-term neonates: does sonography still play a role? Pediatr Radiol. 2006;36:636-646. 229. Chau V, Poskitt KJ, Sargent MA, et al. Comparison of computer tomography and magnetic resonance imaging scans on the third day of life in term newborns with neonatal encephalopathy. Pediatrics. 2009;123:319-326. 230. Glass HC, Bonifacio SL, Shimotake T, et al. Neurocritical care for neonates. Curr Treat Options Neurol. 2011;13:574-589. 232. de Vries LS, Connell JA, Dubowitz LM, et al. Neurological, electrophysiological and MRI abnormalities in infants with extensive cystic leukomalacia. Neuropediatrics. 1987;18:61-66.231. Dubowitz LM, Bydder GM, Mushin J. Developmental sequence of periventricular leukomalacia. Correlation of ultrasound, clinical, and nuclear magnetic resonance functions. Arch Dis Child. 1985;60:349-355. 233. Byrne P, Welch R, Johnson MA, et al. Serial magnetic resonance imaging in neonatal hypoxic–ischemic encephalopathy. J Pediatr. 1990;117:694-700. 234. Keeney SE, Adcock EW, McArdle CB. Prospective observations of 100 high-risk neonates by high-field (1.5 Tesla) magnetic resonance imaging of the central nervous system. II. Lesions associated with hypoxic–ischemic encephalopathy. Pediatrics. 1991;87:431-438. 235. Grossman R, Novak G, Patel M, et al. MRI in neonatal dural sinus thrombosis. Pediatr Neurol. 1993;9:235-238. 236. Rollins NK, Morriss MC, Evans D, et al. The role of early MR in the evaluation of the term infant with seizures. AJNR Am J Neuroradiol. 1994;15:239-248. 237. Kuenzle C, Baenziger O, Martin E, et al. Prognostic value of early MR imaging in term infants with severe perinatal asphyxia. Neuropediatrics. 1994;25:191-200. 238. Blankenberg FG, Loh NN, Bracci P, et al. Sonography, CT, and MR imaging: a prospective comparison of neonates with suspected intracranial ischemia and hemorrhage. AJNR Am J Neuroradiol. 2000;21:213-218. 239. Martin E, Barkovich AJ. Magnetic resonance imaging in perinatal asphyxia. Arch Dis Child. 1995;72:F62-F70. 240. Rutherford MA, Pennock JM, Schwieso JE, et al. Hypoxic ischaemic encephalopathy: early magnetic resonance imaging fundings and their evolution. Neuropediatrics. 1995;26:183191. 241. Rutherford M, Pennock J, Schwieso J, et al. Hypoxic-ischaemic encephalopathy: early and late magnetic resonance imaging findings in relation to outcome. Arch Dis Child. 1996;75:F145-F151.

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Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy 288. Lovblad KO, Laubach HJ, Baird AE, et al. Clinical experience with diffusion-weighted MR in patients with acute stroke. AJNR Am J Neuroradiol. 1998;19:1061-1066. 289. Burdette JH, Ricci PE, Petitti N, et al. Cerebral infarction: time course of signal intensity changes on diffusion-weighted MR images. AJR Am J Roentgenol. 1998;171:791-795. 290. Schwamm LH, Koroshetz WJ, Sorensen AG, et al. Time course of lesion development in patients with acute stroke: serial diffusionand hemodynamic-weighted magnetic resonance imaging. Stroke. 1998;29:2268-2276. 291. Baird AE, Warach S. Magnetic resonance imaging of acute stroke. J Cereb Blood Flow Metab. 1998;18:583-609. 292. Yoneda Y, Tokui K, Hamihara T, et al. Diffusion-weighted magnetic resonance imaging: detection of ischemic injury 39 minutes after onset in a stroke patient. Ann Neurol. 1999;45:794-797. 293. Takeoka M, Soman TB, Yoshii A, et al. Diffusion-weighted images in neonatal cerebral hypoxic–ischemic injury. Pediatr Neurol. 2002;26:274-281. 294. Wolf RL, Zimmerman RA, Clancy R, et al. Quantitative apparent diffusion coefficient measurements in term neonates for early detection of hypoxic–ischemic brain injury: initial experience. Radiology. 2001;218:825-833. 295. Soul JS, Robertson RL, Tzika AA, et al. Time course of changes in diffusion-weighted magnetic resonance imaging in a case of neonatal encephalopathy with defined onset and duration of hypoxic–ischemic insult. Pediatrics. 2001;108:1211-1214. 296. Hunt RW, Neil JJ, Coleman LT, et al. Apparent diffusion coefficient in the posterior limb of the internal capsule predicts outcome after perinatal asphyxia. Pediatrics. 2004;114:999-1003. 297. Roelants-Van Rijn AM, Nikkels PGJ, Groenendaal F, et al. Neonatal diffusion-weighted MR imaging: relation with histopathology or follow-up MR examination. Neuropediatrics. 2001;32:286-294. 298. McKinstry RC, Miller JH, Snyder AZ, et al. A prospective, longitudinal diffusion tensor imaging study of brain injury in newborns. Neurology. 2002;59:824-833. 299. De Vries LS, Van der Grond J, Van Haastert IC, et al. Prediction of outcome in new-born infants with arterial ischaemic stroke using diffusion-weighted magnetic resonance imaging. Neuropediatrics. 2005;36:12-20. 300. Miller SP. Newborn brain injury: looking back to the fetus. Ann Neurol. 2007;61:285-287. 301. Malik GK, Trivedi R, Gupta RK, et al. Serial quantitative diffusion tensor MRI of the term neonates with hypoxic–ischemic encephalopathy (HIE). Neuropediatrics. 2006;37:337-343. 302. Copen WA, Schwamm LH, Gonzalez G, et al. Ischemic stroke: effects of etiology and patient age on the time course of the core apparent diffusion coefficient. Neuroradiology. 2001;221:27-34. 303. Bednarek N, Mathur A, Inder T, et al. Impact of therapeutic hypothermia on MRI diffusion changes in neonatal encephalopathy. Neurology. 2012;78:1420-1427. 304. Meng S, Qiao M, Scobie K, et al. Evolution of magnetic resonance imaging changes associated with cerebral hypoxia-ischemia and a relatively selective white matter injury in neonatal rats. Pediatr Res. 2006;59:554-559. 305. Hope PL, Costello AM, Cady EB, et al. Cerebral energy metabolism studied with phosphorus NMR spectroscopy in normal and birth-asphyxiated infants. Lancet. 1984;2:366-370. 306. Wyatt JS, Edwards AD, Azzopardi D, et al. Magnetic resonance and near infrared spectroscopy for investigation of perinatal hypoxic-ischaemic brain injury. Arch Dis Child. 1989;64:953-963. 307. Roth SC, Azzopardi D, Aldridge R, et al. Progression of changes in cerebral energy metabolism in newborn infants studied by 31P magnetic resonance spectroscopy (MRS) following birth asphyxia. Neuropediatrics. 1991;22:169-170. 308. Roth SC, Edwards AD, Cady EB, et al. Relation between cerebral oxidative metabolism following birth asphyxia, and neurodevelopmental outcome and brain growth at one year. Dev Med Child Neurol. 1992;34:285-295. 309. Azzopardi D, Wyatt JS, Cady EB, et al. Prognosis of newborn infants with hypoxic–ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res. 1989;25:445-451. 310. Cady EB. Phosphorus and proton magnetic resonance spectroscopy of the brain of the newborn human infant. In: Bachelard H, ed. Magnetic Resonance Spectroscopy and Imaging in Neurochemistry. New York: Plenum Press Div Plenum Publishing Corp; 1997:289-327.

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311. Martin E, Buchli R, Ritter S, et al. Diagnostic and prognostic value of cerebral 31P magnetic resonance spectroscopy in neonates with perinatal asphyxia. Pediatr Res. 1996;40:749-758. 312. Roth SC, Baudin J, Cady E, et al. Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years. Dev Med Child Neurol. 1997;39: 718-725. 313. Robertson NJ, Cox IJ, Cowan FM, et al. Cerebral intracellular lactic alkalosis persisting months after neonatal encephalopathy measured by magnetic resonance spectroscopy. Pediatr Res. 1999;46: 287-296. 314. Robertson NJ, Cowan FM, Cox IJ, et al. Brain alkaline intracellular pH after neonatal encephalopathy. Ann Neurol. 2002;52:732-742. 315. Pi RB, Li WM, Lee NTK, et al. Minocycline prevents glutamateinduced apoptosis of cerebellar granule neurons by differential regulation of p38 and Akt pathways. J Neurochem. 2004;91: 1219-1230. 316. Peden CJ, Rutherford MA, Sargentoni J, et al. Proton spectroscopy of the neonatal brain following hypoxic-ischaemic injury. Dev Med Child Neurol. 1993;35:502-510. 317. Groenendaal F, Veenhoven RH, Van Der Grond J, et al. Cerebral lactate and N-acetyl-aspartate/choline ratios in asphyxiated full-term neonates demonstrated in vivo using proton magnetic resonance spectroscopy. Pediatr Res. 1994;35:148-151. 318. Hanrahan JD, Sargentoni J, Azzopardi D, et al. Cerebral metabolism within 18 hours of birth asphyxia: a proton magnetic resonance spectroscopy study. Pediatr Res. 1996;39:584-590. 319. Leth H, Toft PB, Peitersen B, et al. Use of brain lactate levels to predict outcome after perinatal asphyxia. Acta Paediatr. 1996;85:859-864. 320. Penrice J, Cady EB, Lorek A, et al. Proton magnetic resonance spectroscopy of the brain in normal preterm and term infants, and early changes after perinatal hypoxia-ischemia. Pediatr Res. 1996;40:6-14. 321. Shu SK, Ashwal S, Holshouser BA, et al. Prognostic value of 1 H-MRS in perinatal CNS insults. Pediatr Neurol. 1997;17:309-318. 322. Holshouser BA, Ashwal S, Luh GY, et al. Proton MR spectroscopy after acute central nervous system injury: outcome prediction in neonates, infants, and children. Radiology. 1997;202:487-496. 323. Ashwal S, Holshouser BA, Tomasi LG, et al. 1H-Magnetic Resonance Spectroscopy determined cerebral lactate and poor neurological outcomes in children with Central Nervous System disease. Ann Neurol. 1997;41:470-481. 324. Hanrahan JD, Cox IJ, Edwards AD, et al. Persistent increases in cerebral lactate concentration after birth asphyxia. Pediatr Res. 1998;44:304-311. 325. Novotny E, Ashwal S, Shevell M. Proton magnetic resonance spectroscopy: an emerging technology in pediatric neurology research. Pediatr Res. 1998;44:1-10. 326. Hanrahan JD, Cox IJ, Azzopardi D, et al. Relation between proton magnetic resonance spectroscopy within 18 hours of birth asphyxia and neurodevelopment at 1 year of age. Dev Med Child Neurol. 1999;41:76-82. 327. Amess PN, Penrice J, Wylezinska M, et al. Early brain proton magnetic resonance spectroscopy and neonatal neurology related to neurodevelopmental outcome at 1 year in term infants after presumed hypoxic-ischaemic brain injury. Dev Med Child Neurol. 1999;41:436-445. 328. Barkovich AJ, Baranski K, Vigneron D, et al. Proton MR spectroscopy for the evaluation of brain injury in asphyxiated, term neonates. AJNR Am J Neuroradiol. 1999;20:1399-1405. 329. Groenendaal F, RoelantsvanRijn AM, vanderGrond J, et al. Glutamate in cerebral tissue of asphyxiated neonates during the first week of life demonstrated in vivo using proton magnetic resonance spectroscopy. Biol Neonate. 2001;79:254-257. 330. Barkovich AJ, Westmark KD, Bedi HS, et al. Proton spectroscopy and diffusion imaging on the first day of life after perinatal asphyxia: preliminary report. AJNR Am J Neuroradiol. 2001;22:1786-1794. 331. Zarifi MK, Astrakas LG, Young Poussaint T, et al. Prediction of adverse outcome with cerebral lactate level and apparent diffusion coefficient in infants with perinatal asphyxia. Radiology. 2002;225:859-870. 332. Roelants-Van Rijn AM, Van Der Grond J, De Vries LS, et al. Value of 1H-MRS using different echo times in neonates with cerebral hypoxia-ischemia. Pediatr Res. 2001;49:356-362.

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Unit IV  Hypoxic-Ischemic and Related Disorders

333. Miller SP, Newton N, Ferriero DM, et al. Predictors of 30-month outcome after perinatal depression: role of proton MRS and socioeconomic factors. Pediatr Res. 2002;52:71-77. 334. Bartha AI, Foster-Barber A, Miller SP, et al. Neonatal encephalopathy: association of cytokines with MR spectroscopy and outcome. Pediatr Res. 2004;56:960-966. 335. Miller SP, Weiss J, Barnwell A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology. 2002;58: 542-548. 336. Khong PL, Tse C, Wong IYC, et al. Diffusion-weighted imaging and proton magnetic resonance spectroscopy in perinatal hypoxic–ischemic encephalopathy: association with neuromotor outcome at 18 months of age. J Child Neurol. 2004;19:872-881. 337. L’Abee C, deVries LS, vanderGrond J, et al. Early diffusionweighted MRI and H-1-magnetic resonance spectroscopy in asphyxiated full-term neonates. Biol Neonate. 2005;88:306-312. 338. da Silva LF, Filho JR, Anes M, et al. Prognostic value of (1)H-MRS in neonatal encephalopathy. Pediatr Neurol. 2006;34:360-366. 339. Shanmugalingam S, Thornton JS, Iwata O, et al. Comparative prognostic utilities of early quantitative magnetic resonance imaging spin-spin relaxometry and proton magnetic resonance spectroscopy in neonatal encephalopathy. Pediatrics. 2006;118: 1467-1477. 340. Zhu W, Zhong W, Qi J, et al. Proton magnetic resonance spectroscopy in neonates with hypoxic–ischemic injury and its prognostic value. Transl Res. 2008;152:225-232. 341. Thayyil S, Chandrasekaran M, Taylor A, et al. Cerebral magnetic resonance biomarkers in neonatal encephalopathy: a metaanalysis. Pediatrics. 2010;125:e382-e395. 342. van Doormaal PJ, Meiners LC, ter Horst HJ, et al. The prognostic value of multivoxel magnetic resonance spectroscopy determined metabolite levels in white and grey matter brain tissue for adverse outcome in term newborns following perinatal asphyxia. Eur Radiol. 2012;22:772-778. 343. Degraeuwe P, Jaspers GJ, Robertson NJ, et al. Magnetic resonance spectroscopy as a prognostic marker in neonatal hypoxic–ischemic encephalopathy: a study protocol for an individual patient data meta-analysis. Syst Rev. 2013;2:96. 344. Wisnowski JL, Wu TW, Reitman AJ, et al. The effects of therapeutic hypothermia on cerebral metabolism in neonates with hypoxic– ischemic encephalopathy: an in vivo 1H-MR spectroscopy study. J Cereb Blood Flow Metab. 2016;36:1075-1086. 345. Volpe JJ, Herscovitch P, Perlman JM, et al. Positron emission tomography in the asphyxiated term newborn: parasagittal impairment of cerebral blood flow. Ann Neurol. 1985;17:287-296. 346. Sladky JT, Rorke LB. Perinatal hypoxic–ischemic spinal cord injury. Pediatr Pathol. 1986;6:87-101. 347. Clancy RR, Sladky JT, Rorke LB. Hypoxic–ischemic spinal cord injury following perinatal asphyxia. Ann Neurol. 1989;25:185-189. 348. Roland EH, Poskitt K, Rodriguez E, et al. Perinatal hypoxic– ischemic thalamic injury: clinical features and neuroimaging. Ann Neurol. 1998;44:161-166. 349. Natsume J, Watanabe K, Kuno F, et al. Clinical, neurophysiologic, and neuropathological features of an infant with brain damage of total asphyxia type (Myers). Pediatr Neurol. 1995;13:61-64. 350. Graybiel AM. The basal ganglia: learning new tricks and loving it. Curr Opin Neurobiol. 2005;15:638-644. 351. Monchi O, Petrides M, Strafella AP, et al. Functional role of the basal ganglia in the planning and execution of actions. Ann Neurol. 2006;59:257-264. 352. Yoshioka H, Mino M, Morikawa Y, et al. Changes in cell proliferation kinetics in the mouse cerebellum after total asphyxia. Pediatrics. 1985;76:965-969. 353. Yoshioka H, Yoshida A, Ochi M, et al. Dendritic development of cortical neurons of mice subjected to total asphyxia: a Golgi-Cox study. Acta Neuropathol. 1986;70:185-189. 354. Roland EH, Jan JE, Hill A, et al. Cortical visual impairment following birth asphyxia. Pediatr Neurol. 1986;2:133-137. 355. Groenendaal F, van Hof-van Duin J. Partial visual recovery in two fullterm infants after perinatal hypoxia. Neuropediatrics. 1990;21:76-78. 356. Muttitt SC, Taylor MJ, Kobayashi JS, et al. Serial visual evoked potentials and outcome in term birth asphyxia. Pediatr Neurol. 1991;7:86-90.

357. Schenk-Rootlieb AJ, van Nieuwenhuizen O, van der Graaf Y, et al. The prevalence of cerebral visual disturbance in children with cerebral palsy. Dev Med Child Neurol. 1992;34:473-480. 358. Mercuri E, Atkinson J, Braddick O, et al. The aetiology of delayed visual maturation: short review and personal findings in relation to magnetic resonance imaging. Eur J Paediatr Neurol. 1997;1:31-34. 359. Mercuri E, Anker S, Guzzetta A, et al. Visual function at school age in children with neonatal encephalopathy and low Apgar scores. Arch Dis Child. 2004;89:F258-F262. 360. Ricci D, Guzzetta A, Cowan F, et al. Sequential neurological examinations in infants with neonatal encephalopathy and low Apgar scores: relationship with brain MRI. Neuropediatrics. 2006;37:148-153. 361. Robertson CM, Morrish DW, Wheler GH, et al. Neonatal encephalopathy: an indicator of early sexual maturation in girls. Pediatr Neurol. 1990;6:102-108. 362. Maller AI, Hankins LL, Yeakley JW, et al. Rolandic type cerebral palsy in children as a pattern of hypoxic–ischemic injury in the full-term neonate. J Child Neurol. 1998;13:313-321. 363. Koeda T, Takeshita K, Kisa T. Bilateral opercular syndrome: an unusual complication of perinatal difficulties. Brain Dev. 1995;17: 193-195. 364. Lou HC. Etiology and pathogenesis of attention-deficit hyperactivity disorder (ADHD): significance of prematurity and perinatal hypoxic-haemodynamic encephalopathy. Acta Paediatr. 1996;85:1266-1271. 365. Toft PB. Prenatal and perinatal striatal injury: a hypothetical cause of attention-deficit-hyperactivity disorder? Pediatr Neurol. 1999;21:602-610. 366. Lou HC, Rosa P, Pryds O, et al. ADHD: increased dopamine receptor availability linked to attention deficit and low neonatal cerebral blood flow. Dev Med Child Neurol. 2004;46:179-183. 367. Sugama S, Ariga M, Hoashi E, et al. Brainstem cranial-nerve lesions in an infant with hypoxic cerebral injury. Pediatr Neurol. 2003;29:256-259. 368. Sarnat HB. Watershed infarcts in the fetal and neonatal brainstem. An aetiology of central hypoventilation, dysphagia, Mobius syndrome and micrognathia. Eur J Paediatr Neurol. 2004;8: 71-87. 369. Martinez-Biarge M, Diez-Sebastian J, Wusthoff CJ, et al. Feeding and communication impairments in infants with central grey matter lesions following perinatal hypoxic-ischaemic injury. Eur J Paediatr Neurol. 2012;16:688-696. 370. Krageloh-Mann I, Helber A, Mader I, et al. Bilateral lesions of thalamus and basal ganglia: origin and outcome. Dev Med Child Neurol. 2002;44:477-484. 371. Yokochi K. Clinical profiles of children with cerebral palsy having lesions of the thalamus, putamen and/or peri-Rolandic area. Brain Dev. 2004;26:227-232. 372. Malamud N. Status marmoratus: a form of cerebral palsy following either birth injury or inflammation of the central nervous system. J Pediatr. 1950;37:610. 373. Yokochi K, Aiba K, Kodama M, et al. Magnetic resonance imaging in athetotic cerebral palsied children. Acta Paediatr Scand. 1991;80:818-823. 374. Himmelmann K, Hagberg G, Wiklund LM, et al. Dyskinetic cerebral palsy: a population-based study of children born between 1991 and 1998. Dev Med Child Neurol. 2007;49:246-251. 375. Polani PE. The natural history of choreoathetoid cerebral palsy. Guys Hosp Rep. 1959;108:32. 376. Paine RS. The evolution of infantile postural reflexes in the presence of chronic brain syndromes. Dev Med Child Neurol. 1964;5:345. 377. Colamaria V, Curatolo P, Cusmai R, et al. Symmetrical bithalamic hyperdensities in asphyxiated full-term newborns: an early indicator of status marmoratus. Brain Dev. 1988;10:57-59. 378. Burke RE, Fahn S, Gold AP. Delayed-onset dystonia in patients with “static” encephalopathy. J Neurol Neurosurg Psychiatry. 1980;43: 789-797. 379. Hanson RA, Berenberg W, Byers RK. Changing motor patterns in cerebral palsy. Dev Med Child Neurol. 1970;12:309-314. 380. Arvidsson J, Hagberg B. Delayed-onset dyskinetic ‘cerebral palsy’—a late effect of perinatal asphyxia? Acta Paediatr Scand. 1990;79:1121-1123.

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy 381. Saint-Hilaire MH, Burke RE, Bressman SB, et al. Delayed-onset dystonia due to perinatal or early childhood asphyxia. Neurology. 1991;41:216-222. 382. Crothers B, Paine RS. The Natural History of Cerebral Palsy. Cambridge: Harvard University Press; 1959. 383. Hagberg B, Hagberg G, Olow I. The changing panorama of cerebral palsy in Sweden 1954-1970. I. Analysis of the general changes. Acta Paediatr Scand. 1975;64:187-192. 384. Kyllerman M, Bager B, Bensch J, et al. Dyskinetic cerebral palsy. I. Clinical categories, associated neurological abnormalities and incidences. Acta Paediatr Scand. 1982;71:543-550. 385. Rosenbloom L. Dyskinetic cerebral palsy and birth asphyxia. Dev Med Child Neurol. 1994;36:285-289. 386. Barnett A, Mercuri E, Rutherford M, et al. Neurological and perceptual-motor outcome at 5–6 years of age in children with neonatal encephalopathy: relationship with neonatal brain MRI. Neuropediatrics. 2002;33:242-248. 387. de Vries LS, Pierrat V, Eken P, et al. Prognostic value of early somatosensory evoked potentials for adverse outcome in full-term infants with birth asphyxia. Brain Dev. 1991;13:320-325. 388. Gonzalez FF, Miller SP. Does perinatal asphyxia impair cognitive function without cerebral palsy? Arch Dis Child Fetal Neonatal Ed. 2006;91:F454-F459. 389. Al-Macki N, Miller SP, Hall N, et al. The spectrum of abnormal neurologic outcomes subsequent to term intrapartum asphyxia. Pediatr Neurol. 2009;41:399-405. 390. Lou HC, Henriksen L, Bruhn P. Focal cerebral hypoperfusion in children with dysphasia and/or attention deficit disorder. Arch Neurol. 1984;41:825-829. 391. Lou HC, Henriksen L, Bruhn P, et al. Striatal dysfunction in attention deficit and hyperkinetic disorder. Arch Neurol. 1989;46:48-52. 392. Lou HC, Henriksen L, Bruhn P. Focal cerebral dysfunction in developmental learning disabilities. Lancet. 1990;335:8-11. 393. Yokochi K. Clinical profiles of subjects with subcortical leukomalacia and border-zone infarction revealed by MR. Acta Paediatr. 1998;87:879-883. 394. Robertson CM, Finer NN, Grace MG. School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Pediatr. 1989;114:753-760. 395. Marlow N, Rose AS, Rands CE, et al. Neuropsychological and educational problems at school age associated with neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2005;90:F380F387. 396. Pappas A, Shankaran S, McDonald SA, et al. Cognitive outcomes after neonatal encephalopathy. Pediatrics. 2015;135:e624-e634. 397. Cordero L Jr, Hon EH. Neonatal bradycardia following nasopharyngeal stimulation. J Pediatr. 1971;78:441-447. 398. Crawford J. Apgar score and neonatal asphyxia [letter]. Lancet. 1982;1:684-685. 399. Catlin EA, Carpenter MW, Brann BS 4th, et al. The Apgar score revisited: influence of gestational age. J Pediatr. 1986;109:865-868. 400. Marlow N. Do we need an Apgar score? Arch Dis Child. 1992;67: 765-767. 401. Hegyi T, Carbone T, Anwar M, et al. The Apgar score and its components in the preterm infant. Pediatrics. 1998;101:77-81. 402. Carter BS, McNabb F, Merenstein GB. Prospective validation of a scoring system for predicting neonatal morbidity after acute perinatal asphyxia. J Pediatr. 1998;132:619-623. 403. Leuthner SR, Das UG. Low Apgar scores and the definition of birth asphyxia. Pediatr Clin North Am. 2004;51:737-745. 404. Stark AR, Adamkin DH, Batton DG, et al. The Apgar score. Pediatrics. 2006;117:1444-1447. 405. Master D, Lie RT, Irgens LM, et al. The association of Apgar score with subsequent death and cerebral palsy: a population-based study in term infants. J Pediatr. 2001;138:798-803. 406. Sykes GS, Molloy PM, Johnson P, et al. Do Apgar scores indicate asphyxia? Lancet. 1982;1:494-496. 407. Silverman F, Suidan J, Wasserman J, et al. The Apgar score: is it enough? Obstet Gynecol. 1985;66:331-336. 408. Dijxhoorn MJ, Visser GH, Touwen BC, et al. Apgar score, meconium and acidaemia at birth in small-for-gestational age infants born at term, and their relation to neonatal neurological morbidity. Br J Obstet Gynaecol. 1987;94:873-879.

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409. Marrin M, Paes BA. Birth asphyxia: does the Apgar score have diagnostic value? Obstet Gynecol. 1988;72:120-123. 410. Ruth VJ, Raivio KO. Perinatal brain damage: predictive value of metabolic acidosis and the Apgar score. BMJ. 1988;297:24-27. 411. King TA, Jackson GL, Josepy AS, et al. The effect of profound umbilical artery acidemia in term neonates admitted to a newborn nursery. J Pediatr. 1998;132:624-629. 412. Lavrijsen SW, Uiterwaal CSPM, Stigter RH, et al. Severe umbilical cord acidemia and neurological outcome in preterm and full-term neonates. Biol Neonate. 2005;88:27-34. 413. Nelson KB, Ellenberg JH. Apgar scores as predictors of chronic neurologic disability. Pediatrics. 1981;68:36-44. 414. Scott H. Outcome of very severe birth asphyxia. Arch Dis Child. 1976;51:712-716. 415. Thomson AJ, Searle M, Russell G. Quality of survival after severe birth asphyxia. Arch Dis Child. 1977;52:620-626. 416. Jain L, Ferre C, Vidyasagar D, et al. Cardiopulmonary resuscitation of apparently stillborn infants: survival and long-term outcome. J Pediatr. 1991;118:778-782. 417. Natarajan G, Shankaran S, Laptook AR, et al. Apgar scores at 10 min and outcomes at 6-7 years following hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2013;98: F473-F479. 418. Dalili H, Nili F, Sheikh M, et al. Comparison of the four proposed Apgar scoring systems in the assessment of birth asphyxia and adverse early neurologic outcomes. PLoS ONE. 2015;10:e0122116. 419. Perlman JM. Intrapartum hypoxic–ischemic cerebral injury and subsequent cerebral palsy: medicolegal issues. Pediatrics. 1997;99:851-857. 420. Ekert P, MacLusky N, Luo XP, et al. Dexamethasone prevents apoptosis in a neonatal rat model of hypoxic–ischemic encephalopathy (HIE) by a reactive oxygen species-independent mechanism. Brain Res. 1997;747:9-17. 421. Shah PS, Beyene J, To T, et al. Postasphyxial hypoxic–ischemic encephalopathy in neonates: outcome prediction rule within 4 hours of birth. Arch Pediatr Adolesc Med. 2006;160:729-736. 422. Ambalavanan N, Carlo WA, Shankaran S, et al. Predicting outcomes of neonates diagnosed with hypoxemic-ischemic encephalopathy. Pediatrics. 2006;118:2084-2093. 423. Fitzhardinge PM, Flodmark O, Fitz CR, et al. The prognostic value of computed tomography as an adjunct to assessment of the term infant with postasphyxial encephalopathy. J Pediatr. 1981;99:777-781. 424. Levene MI, Sands C, Grindulis H, et al. Comparison of two methods of predicting outcome in perinatal asphyxia. Lancet. 1986;1:67-69. 425. Shankaran S, Woldt E, Koepke T, et al. Acute neonatal morbidity and long-term central nervous system sequelae of perinatal asphyxia in term infants. Early Hum Dev. 1991;25:135-148. 426. Perlman JM, Tack ED. Renal injury in the asphyxiated newborn infant: relationship to neurologic outcome. J Pediatr. 1988;113: 875-879. 427. Lanzi G, Fazzi E, Gerardo A, et al. Early predictors of neurodevelopmental outcome at 12-36 months in very lowbirthweight infants. Brain Dev. 1990;12:482-487. 428. Amiel-Tison C, Ellison P. Birth asphyxia in the fullterm newborn: early assessment and outcome. Dev Med Child Neurol. 1986;28:671-682. 429. Nelson KB, Ellenberg JH. The asymptomatic newborn and risk of cerebral palsy. Am J Dis Child. 1987;141:1333-1335. 430. Ellenberg JH, Nelson KB. Cluster of perinatal events identifying infants at high risk for death or disability. J Pediatr. 1988;113: 546-552. 431. Robertson CM, Finer NN. Educational readiness of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Dev Behav Pediatr. 1988;9:298-306. 432. Ishikawa T, Ogawa Y, Kanayama M, et al. Long-term prognosis of asphyxiated full-term neonates with CNS complications. Brain Dev. 1987;9:48-53. 433. De Souza SW, Richards B. Neurological sequelae in newborn babies after perinatal asphyxia. Arch Dis Child. 1978;53:564-569. 434. Fitzhardinge PM, Flodmark O, Ashby S. The prognostic value of computed tomography of the brain in asphyxiated premature infants. J Pediatr. 1982;100:476-481.

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Unit IV  Hypoxic-Ischemic and Related Disorders

435. Finer NN, Robertson CM, Peters KL, et al. Factors affecting outcome in hypoxic–ischemic encephalopathy in term infants. Am J Dis Child. 1983;137:21-25. 436. Yudkin PL, Johnson A, Clover LM, et al. Clustering of perinatal markers of birth asphyxia and outcome at age five years. Br J Obstet Gynaecol. 1994;101:774-781. 437. Wolf MJ, Wolf B, Bijleveld C, et al. Neurodevelopmental outcome in babies with a low Apgar score from Zimbabwe. Dev Med Child Neurol. 1997;39:821-826. 438. Wayenberg J-L, Dramaix M, Vermeylen D, et al. Neonatal outcome after birth asphyxia: early indicators of prognosis. Prenat Neonat Med. 1998;3:482-489. 439. Caravale B, Allemand F, Libenson MH. Factors predictive of seizures and neurologic outcome in perinatal depression. Pediatr Neurol. 2003;29:18-25. 440. Dixon G, Badawi N, Kurinczuk JJ, et al. Early developmental outcomes after newborn encephalopathy. Pediatrics. 2002;109:26-33. 441. Badawi N, Felix JF, Kurinezuk JF, et al. Cerebral palsy following term newborn encephalopathy: a population-based study. Dev Med Child Neurol. 2005;47:293-298. 442. Miller SP, Latal B, Clark H, et al. Clinical signs predict 30-month neurodevelopmental outcome after neonatal encephalopathy. Am J Obstet Gynecol. 2004;190:93-99. 443. Miller SP, Ferriero DM, Leonard C, et al. Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome. J Pediatr. 2005;147:609-616. 444. Lindstrom K, Lagerroos P, Gillberg C, et al. Teenage outcome after being born at term with moderate neonatal encephalopathy. Pediatr Neurol. 2006;35:268-274. 445. Ellis M, Manandhar N, Shrestha PS, et al. Outcome at 1 year of neonatal encephalopathy in Kathmandu, Nepal. Dev Med Child Neurol. 1999;41:689-695. 446. Van Kooij BJ, Van Handel M, Uiterwaal CS, et al. Corpus callosum size in relation to motor performance in 9- to 10-year-old children with neonatal encephalopathy. Pediatr Res. 2008;63:103-108. 447. van Handel M, Swaab H, de Vries LS, et al. Behavioral outcome in children with a history of neonatal encephalopathy following perinatal asphyxia. J Pediatr Psychol. 2010;35:286-295. 448. van Handel M, de Sonneville L, de Vries LS, et al. Specific memory impairment following neonatal encephalopathy in term-born children. Dev Neuropsychol. 2012;37:30-50. 449. Nelson KB, Ellenberg JH. Neonatal signs as predictors of cerebral palsy. Pediatrics. 1979;64:225-232. 450. Nelson KB, Broman SH. Perinatal risk factors in children with serious motor and mental handicaps. Ann Neurol. 1977;2:371377. 451. Curtis PD, Matthews TG, Clarke TA, et al. Neonatal seizures: the Dublin Collaborative Study. Arch Dis Child. 1988;63:1065-1068. 452. Minchom P, Niswander K, Chalmers I, et al. Antecedents and outcome of very early neonatal seizures in infants born at or after term. Br J Obstet Gynaecol. 1987;94:431-439. 453. Tekgul H, Gauvreau K, Soul J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics. 2006;117:1270-1280. 454. al Naqeeb N, Edwards AD, Cowan FM, et al. Assessment of neonatal encephalopathy by amplitude-integrated electroencephalography. Pediatrics. 1999;103:1263-1271. 455. Douglass LM, Wu JY, Rosman NP, et al. Burst suppression electroencephalogram pattern in the newborn: predicting the outcome. J Child Neurol. 2002;17:403-408. 456. Osredkar D, Toet MC, vanRooij LGM, et al. Sleep-wake cycling on amplitude-integrated electroencephalography in term newborns with hypoxic–ischemic encephalopathy. Pediatrics. 2005;115:327-332. 457. Murray DM, Boylan GB, Ryan CA, et al. Early EEG findings in hypoxic–ischemic encephalopathy predict outcomes at 2 years. Pediatrics. 2009;124:e459-e467. 458. Hellstrom-Westas L, Rosen I. Continuous brain-function monitoring: state of the art in clinical practice. Semin Fetal Neonatal Med. 2006;11:503-511. 459. Hellstrom-Westas L. Monitoring brain function with aEEG in term asphyxiated infants before and during cooling. Acta Paediatr. 2013;102:678-679.

460. Shepherd AJ, Saunders KJ, McCulloch DL, et al. Prognostic value of flash visual evoked potentials in preterm infants. Dev Med Child Neurol. 1999;41:9-15. 461. Kato T, Watanabe K. Visual evoked potential in the newborn: does it have predictive value? Semin Fetal Neonatal Med. 2006;11:459-463. 462. Hrbek A, Karlberg P, Kjellmer I, et al. Clinical application of evoked electroencephalographic responses in newborn infants. I: perinatal asphyxia. Dev Med Child Neurol. 1977;19:34-44. 463. Willis J, Duncan C, Bell R. Short-latency somatosensory evoked potentials in perinatal asphyxia. Pediatr Neurol. 1987;3:203-207. 464. Gibson NA, Graham M, Levene MI. Somatosensory evoked potentials and outcome in perinatal asphyxia. Arch Dis Child. 1992;67(SI):393-398. 465. de Vries LS, Eken P, Pierrat V, et al. Prediction of neurodevelopmental outcome in the preterm infant—short latency cortical somatosensory evoked potentials compared with cranial ultrasound. Arch Dis Child. 1992;67:1177-1181. 466. Majnemer A, Rosenblatt B. Prediction of outcome at school entry in neonatal intensive care unit survivors, with use of clinical and electrophysiologic techniques. J Pediatr. 1995;127:823-830. 467. Vanhatalo S, Lauronen L. Neonatal SEP—back to bedside with basic science. Semin Fetal Neonatal Med. 2006;11:464-470. 468. Siegel MJ, Shackelford GD, Perlman JM, et al. Hypoxic–ischemic encephalopathy in term infants: diagnosis and prognosis evaluated by ultrasound. Radiology. 1984;152:395-399. 469. Babcock DS, Ball W Jr. Postasphyxial encephalopathy in full-term infants: ultrasound diagnosis. Radiology. 1983;148:417-423. 470. Volpe JJ. Value of MR in definition of the neuropathology of cerebral palsy in vivo. AJNR Am J Neuroradiol. 1992;13:79-83. 471. Estan J, Hope P. Unilateral neonatal cerebral infarction in full term infants. Arch Dis Child. 1997;76:F88-F93. 472. Haataja L, Mercuri E, Guzzetta A, et al. Neurologic examination in infants with hypoxic–ischemic encephalopathy at age 9 to 14 months: use of optimality scores and correlation with magnetic resonance imaging findings. J Pediatr. 2001;138:332-337. 473. Vermeulen RJ, van Schie PE, Hendrikx L, et al. Diffusion-weighted and conventional MR imaging in neonatal hypoxic ischemia: two-year follow-up study. Radiology. 2008;249:631-639. 474. Rutherford M, Malamateniou C, McGuinness A, et al. Magnetic resonance imaging in hypoxic-ischaemic encephalopathy. Early Hum Dev. 2010;86:351-360. 475. Alderliesten T, de Vries LS, Benders MJ, et al. MR imaging and outcome of term neonates with perinatal asphyxia: value of diffusion-weighted MR imaging and (1)H MR spectroscopy. Radiology. 2011;261:235-242. 476. Rutherford M, Ramenghi LA, Edwards AD, et al. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol. 2010;9:39-45. 477. Cheong JL, Coleman L, Hunt RW, et al. Prognostic utility of magnetic resonance imaging in neonatal hypoxic–ischemic encephalopathy: substudy of a randomized trial. Arch Pediatr Adolesc Med. 2012;166:634-640. 478. van Laerhoven H, de Haan TR, Offringa M, et al. Prognostic tests in term neonates with hypoxic–ischemic encephalopathy: a systematic review. Pediatrics. 2013;131:88-98. 479. Kato T, Nishina M, Matsushita K, et al. Neuronal maturation and N-acetyl-L-aspartic acid development in human fetal and child brains. Brain Dev. 1997;19:131-133. 480. Urenjak J, Williams SR, Gadian DG, et al. Specific expression of N-acetylaspartate in neurons, oligodendrocyte-type-2 astrocyte progenitors, and immature oligodendrocytes in vitro. J Neurochem. 1992;59:55-61. 481. Groenendaal F, van der Grond J, Witkamp TD, et al. Proton magnetic resonance spectroscopic imaging in neonatal stroke. Neuropediatrics. 1995;26:243-248. 482. Corbo ET, Bartnik-Olson BL, Machado S, et al. The effect of whole-body cooling on brain metabolism following perinatal hypoxic–ischemic injury. Pediatr Res. 2012;71:85-92. 483. Ancora G, Testa C, Grandi S, et al. Prognostic value of brain proton MR spectroscopy and diffusion tensor imaging in newborns with hypoxic–ischemic encephalopathy treated by brain cooling. Neuroradiology. 2013;55:1017-1025.

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy 484. Flodmark O, Becker LE, Harwood-Nash DC, et al. Correlation between computed tomography and autopsy in premature and full-term neonates that have suffered perinatal asphyxia. Radiology. 1980;137:93-103. 485. Adsett DB, Fitz CR, Hill A. Hypoxic-ischaemic cerebral injury in the term newborn: correlation of CT findings with neurological outcome. Dev Med Child Neurol. 1985;27:155-160. 486. Lipp-Zwahlen AE, Deonna T, Chrzanowski R, et al. Temporal evolution of hypoxic-ischaemic brain lesions in asphyxiated full-term newborns as assessed by computerized tomography. Neuroradiology. 1985;27:138-144. 487. Lipp-Zwahlen AE, Deonna T, Micheli JL, et al. Prognostic value of neonatal CT scans in asphyxiated term babies: low density score compared with neonatal neurological signs. Neuropediatrics. 1985;16:209-217. 488. Lipper EG, Voorhies TM, Ross G, et al. Early predictors of oneyear outcome for infants asphyxiated at birth. Dev Med Child Neurol. 1986;28:303-309. 489. Bada HS, Hajjar W, Chua C, et al. Noninvasive diagnosis of neonatal asphyxia and intraventricular hemorrhage by Doppler ultrasound. J Pediatr. 1979;95:775-779. 490. Ando Y, Takashima S, Takeshita K. Cerebral blood flow velocities in postasphyxial term neonates. Brain Dev. 1983;5:529-532. 491. van Bel F, van de Bor M, Stijnen T, et al. Cerebral blood flow velocity pattern in healthy and asphyxiated newborns: a controlled study. Eur J Pediatr. 1987;146:461-467. 492. Archer LN, Levene MI, Evans DH. Cerebral artery Doppler ultrasonography for prediction of outcome after perinatal asphyxia. Lancet. 1986;2:1116-1118. 493. Ramaekers VT, Casaer P. Defective regulation of cerebral oxygen transport after severe birth asphyxia. Dev Med Child Neurol. 1990;32:56-62. 494. Levene MI, Fenton AC, Evans DH, et al. Severe birth asphyxia and abnormal cerebral blood-flow velocity. Dev Med Child Neurol. 1989;31:427-434. 495. Morrison FK, Patel NB, Howie PW, et al. Neonatal cerebral arterial flow velocity waveforms in term infants with and without metabolic acidosis at delivery. Early Hum Dev. 1995;42:155-168. 496. Ilves P, Talvik R, Talvik T. Changes in Doppler ultrasonography in asphyxiated term infants with hypoxic-ischaemic encephalopathy. Acta Paediatr. 1998;87:680-684. 497. Jongeling BR, Badawi N, Kurinczuk JJ, et al. Cranial ultrasound as a predictor of outcome in term newborn encephalopathy. Pediatr Neurol. 2002;26:37-42. 498. Ilves P, Lintrop M, Metsvaht T, et al. Cerebral blood-flow velocities in predicting outcome of asphyxiated newborn infants. Acta Paediatr. 2004;93:523-528. 499. Marks KA, Mallard EC, Roberts I, et al. Delayed vasodilation and altered oxygenation after cerebral ischemia in fetal sheep. Pediatr Res. 1995;39:48-54. 500. Wyatt JS. Near infrared spectroscopy in asphyxiated brain injury. Clin Perinatol. 1993;20:369-378. 501. Meek JH, Elwell CE, McCormick DC, et al. Abnormal cerebral haemodynamics in perinatally asphyxiated neonates related to outcome. Arch Dis Child. 1999;81:F110-F115. 502. Skov I, Pryds O, Greisen G, et al. Estimation of cerebral venous saturation in newborn infants by near infrared spectroscopy. Pediatr Res. 1993;33:52-55. 503. Ancora G, Maranella E, Grandi S, et al. Early predictors of short term neurodevelopmental outcome in asphyxiated cooled infants. A combined brain amplitude integrated electroencephalography and near infrared spectroscopy study. Brain Dev. 2013;35:26-31. 504. Lemmers PM, Zwanenburg RJ, Benders MJ, et al. Cerebral oxygenation and brain activity after perinatal asphyxia: does hypothermia change their prognostic value? Pediatr Res. 2013;74:180-185. 505. Pryds O, Greisen G, Lou H, et al. Vasoparalysis associated with brain damage in asphyxiated term infants. J Pediatr. 1990;117:119-125. 506. Rosenbaum JL, Almli CR, Yundt KD, et al. Higher neonatal cerebral blood flow correlates with worse childhood neurologic outcome. Neurology. 1997;49:1035-1041. 507. Thorngren-Jerneck K, Ohlsson T, Sandell A, et al. Cerebral glucose metabolism measured by positron emission tomography in term

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newborn infants with hypoxic ischemic encephalopathy. Pediatr Res. 2001;49:495-501. 508. Shankaran S, Szego E, Eizert D, et al. Severe bronchopulmonary dysplasia. Predictors of survival and outcome. Chest. 1984;86: 607-610. 509. Sarkar S, Barks JD, Bhagat I, et al. Pulmonary dysfunction and therapeutic hypothermia in asphyxiated newborns: whole body versus selective head cooling. Am J Perinatol. 2009;26:265-270. 510. Jacobs SE, Berg M, Hunt R, et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013;(1):CD003311. 511. Gagnon MH, Wintermark P. Effect of persistent pulmonary hypertension on brain oxygenation in asphyxiated term newborns treated with hypothermia. J Matern Fetal Neonatal Med. 2016;29:2049-2055. 512. Kennedy C, Grave GD, Jehle JW. Effect of hyperoxia on the cerebral circulation of the newborn puppy. Pediatr Res. 1971;5:659. 513. Klinger G, Beyene J, Shah P, et al. Do hyperoxaemia and hypocapnia add to the risk of brain injury after intrapartum asphyxia? Arch Dis Child. 2005;90:F49-F52. 514. Kapadia VS, Chalak LF, Dupont TL, et al. Perinatal asphyxia with hyperoxemia within the first hour of life is associated with moderate to severe hypoxic–ischemic encephalopathy. J Pediatr. 2013;163:949-954. 515. Saugstad OD, Ramji S, Irani SF, et al. Resuscitation of newborn infants with 21% or 100% oxygen: follow-up at 18 to 24 months. Pediatrics. 2003;112:296-300. 516. Vento M, Asensi M, Sastre J, et al. Resuscitation with room air instead of 100% oxygen prevents oxidative stress in moderately asphyxiated term neonates. Pediatrics. 2001;107:642-647. 517. Vento M, Asensi M, Sastre J, et al. Oxidative stress in asphyxiated term infants resuscitated with 100% oxtygen. J Pediatr. 2003;142: 240-246. 518. Saugstad OD, Ramji S, Rootwelt T, et al. Response to resuscitation of the newborn: early prognostic variables. Acta Paediatr. 2005;94:890-895. 519. Saugstad OD, Ramji S, Vento M. Oxygen for newborn resuscitation: how much is enough? Pediatrics. 2006;118:789-792. 520. Higgins RD, Bancalari E, Willinger M, et al. Executive summary of the workshop on oxygen in neonatal therapies: controversies and opportunities for research. Pediatrics. 2007;119:790-796. 521. Torres-Cuevas I, Parra-Llorca A, Sanchez-Illana A, et al. Oxygen and oxidative stress in the perinatal period. Redox Biol. 2017;12:674-681. 522. Rabi Y, Rabi D, Yee W. Room air resuscitation of the depressed newborn: a systematic review and meta-analysis. Resuscitation. 2007;72:353-363. 523. Solberg R, Longini M, Proietti F, et al. Resuscitation with supplementary oxygen induces oxidative injury in the cerebral cortex. Free Radic Biol Med. 2012;53:1061-1067. 524. Perlman JM, Wyllie J, Kattwinkel J, et al. Part 7: Neonatal Resuscitation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2015;132:S204-S241. 525. Roberts BW, Karagiannis P, Coletta M, et al. Effects of PaCO2 derangements on clinical outcomes after cerebral injury: a systematic review. Resuscitation. 2015;91:32-41. 526. Hansen G, Al Shafouri N, Narvey M, et al. High blood carbon dioxide variability and adverse outcomes in neonatal hypoxic ischemic encephalopathy. J Matern Fetal Neonatal Med. 2016;29:680-683. 527. Cassady G. Transcutaneous monitoring in the newborn infant. J Pediatr. 1983;103:837-848. 528. Peabody JL, Emery JR. Noninvasive monitoring of blood gases in the newborn. Clin Perinatol. 1985;12:147-160. 529. Hansen TN, Tooley WH. Skin surface carbon dioxide tension in sick infants. Pediatrics. 1979;64:942-945. 530. Merritt TA, Liyamasawad S, Boettrich C, et al. Skin-surface CO2 measurement in sick preterm and term infants. J Pediatr. 1981;99:782-786. 531. Hunt CE. Cardiorespiratory monitoring. Clin Perinatol. 1991;18: 473-495. 532. Kaiser JR, Gauss CH, Williams DK. The effects of hypercapnia on cerebral autoregulation in ventilated very low birth weight infants. Pediatr Res. 2005;58:931-935.

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Unit IV  Hypoxic-Ischemic and Related Disorders

533. Reivich M. Arterial pCO2 and cerebral hemodynamics. Am J Physiol. 1964;206:25. 534. Haggendal E, Johansson B. Effects of arterial carbon dioxide tension and oxygen saturation on cerebral blood flow autoregulation in dogs. Acta Physiol Scand Suppl. 1965;258:27-53. 535. Davis SM, Ackerman RH, Correia JA, et al. Cerebral blood flow and cerebrovascular CO2 reactivity in stroke-age normal controls. Neurology. 1983;33:391-399. 536. Purves MJ, James IM. Observations on the control of cerebral blood flow in the sheep fetus and newborn lamb. Circ Res. 1969;25:651-667. 537. Reivich M, Brann AW Jr, Shapiro H, et al. Reactivity of cerebral vessels to CO2 in the newborn rhesus monkey. Eur Neurol. 1971;6:132-136. 538. Shapiro HM, Greenberg JH, Naughton KV, et al. Heterogeneity of local cerebral blood flow-PaCO2 sensitivity in neonatal dogs. J Appl Physiol. 1980;49:113-118. 539. Batton DG, Hellmann J, Hernandez MJ, et al. Regional cerebral blood flow, cerebral blood velocity, and pulsatility index in newborn dogs. Pediatr Res. 1983;17:908-912. 540. Hansen NB, Brubakk AM, Bratlid D, et al. The effects of variations in PaCO2 on brain blood flow and cardiac output in the newborn piglet. Pediatr Res. 1984;18:1132-1136. 541. Young RS, Yagel SK. Cerebral physiological and metabolic effects of hyperventilation in the neonatal dog. Ann Neurol. 1984;16: 337-342. 542. Reuter JH. Cerebral blood flow and cerebral oxygen metabolic rate during hyperventilation in the newborn dog. Pediatr Res. 1985;19:360. 543. Gleason CA, Hamm C, Jones MD Jr. Cerebral blood flow, oxygenation, and carbohydrate metabolism in immature fetal sheep in utero. Am J Physiol. 1989;256:R1264-R1268. 544. Gleason CA, Short BL, Jones MD Jr. Cerebral blood flow and metabolism during and after prolonged hypocapnia in newborn lambs. J Pediatr. 1989;115:309-314. 545. Rosenberg AA, Jones MD Jr, Traystman RJ, et al. Response of cerebral blood flow to changes in PCO2 in fetal, newborn, and adult sheep. Am J Physiol. 1982;242:H862-H866. 546. Kamei A, Ozaki T, Takashima S. Monitoring of the intracranial hemodynamics and oxygenation during and after hyperventilation in newborn rabbits with near-infrared spectroscopy. Pediatr Res. 1994;35:334-338. 547. Vannucci RC, Towfighi J, Heitjan DF, et al. Carbon dioxide protects the perinatal brain from hypoxic–ischemic damage: an experimental study in the immature rat. Pediatrics. 1995;95: 868-874. 548. Vannucci RC, Brucklacher RM, Vannucci SJ. Effect of carbon dioxide on cerebral metabolism during hypoxia-ischemia in the immature rat. Pediatr Res. 1997;42:24-29. 549. Vannucci RC. Interventions for perinatal hypoxic–ischemic encephalopathy. Pediatrics. 1997;100:1004-1014. 550. Pryds O, Greisen G, Lou H, et al. Heterogeneity of cerebral vasoreactivity in preterm infants supported by mechanical ventilation. J Pediatr. 1989;115:638-645. 551. Pryds O, Greisen G. Effect of PaCO 2 and haemoglobin concentration on day to day variation of CBF in preterm neonates. Acta Paediatr Scand Suppl. 1989;360:33-36. 552. Wyatt JS, Edwards AD, Cope M, et al. Response of cerebral blood volume to changes in arterial carbon dioxide tension in preterm and term infants. Pediatr Res. 1991;29:553-557. 553. Muller AM, Morales C, Briner J, et al. Loss of CO2 reactivity of cerebral blood flow is associated with severe brain damage in mechanically ventilated very low birth weight infants. Eur J Paediatr Neurol. 1997;5:157-163. 554. Pryds O, Edwards AD. Cerebral blood flow in the newborn infant. Arch Dis Child. 1996;74:F63-F69. 555. Victor S, Appleton RE, Beirne M, et al. Effect of carbon dioxide on background cerebral electrical activity and fractional oxygen extraction in very low birth weight infants just after birth. Pediatr Res. 2005;58:579-585. 556. Pappas A, Shankaran S, Laptook AR, et al. Hypocarbia and adverse outcome in neonatal hypoxic–ischemic encephalopathy. J Pediatr. 2011;158:752-758 e751. 557. Nadeem M, Murray D, Boylan G, et al. Blood carbon dioxide levels and adverse outcome in neonatal hypoxic–ischemic encephalopathy. Am J Perinatol. 2010;27:361-365.

558. Kitterman JA, Phibbs RH, Tooley WH. Aortic blood pressure in normal newborn infants during the first 12 hours of life. Pediatrics. 1969;44:959-968. 559. Hall RT, Oliver TK Jr. Aortic blood pressure in infants admitted to a neonatal intensive care unit. Am J Dis Child. 1971;121:145-147. 560. Modanlou H, Yeh SY, Siassi B, et al. Direct monitoring of arterial blood pressure in depressed and normal newborn infants during the first hour of life. J Pediatr. 1974;85:553-559. 561. Bucci G, Scalamandre A, Savignoni PG, et al. The systemic systolic blood pressure of newborns with low weight. A multiple regression analysis. Acta Paediatr Scand Suppl. 1972;229:1-26. 562. Versmold HT, Kitterman JA, Phibbs RH, et al. Aortic blood pressure during the first 12 hours of life in infants with birth weight 610 to 4,220 grams. Pediatrics. 1981;67:607-613. 563. Adams JH, Brierley JB, Connor RC, et al. The effects of systemic hypotension upon the human brain. Clinical and neuropathological observations in 11 cases. Brain. 1966;89:235-268. 564. Sonesson SE, Broberger U. Arterial blood pressure in the very low birthweight neonate. Evaluation of an automatic oscillometric technique. Acta Paediatr Scand. 1987;76:338-341. 565. van Ravenswaaij-Arts CM, Hopman JC, Kollée LA. Influence of behavioural state on blood pressure in preterm infants during the first 5 days of life. Acta Paediatr Scand. 1989;78:358-363. 566. Guignard JP, Gouyon JB, Adelman RD. Arterial hypertension in the newborn infant. Biol Neonate. 1989;55:77-83. 567. Shortland DB, Evans DH, Levene MI. Blood pressure measurements in very low birth weight infants over the first week of life. J Perinat Med. 1988;16:93-97. 568. Weindling AM. Blood pressure monitoring in the newborn. Arch Dis Child. 1989;64:444-447. 569. Emery EF, Greenough A, Yuksel B. Effect of gender on blood pressure levels of very low birthweight infants in the first 48 hours of life. Early Hum Dev. 1993;31:209-216. 570. Hegyi T, Anwar M, Carbone MT, et al. Blood pressure ranges in premature infants: II. The first week of life. Pediatrics. 1996;97: 336-342. 571. Watkins AM, West CR, Cooke RW. Blood pressure and cerebral haemorrhage and ischaemia in very low birthweight infants. Early Hum Dev. 1989;19:103-110. 572. Laughon M, Bose C, Allred E, et al. Factors associated with treatment for hypotension in extremely low gestational age newborns during the first postnatal week. Pediatrics. 2007;119:273-280. 573. Barrington K. Time for pressure tactics. Pediatrics. 2007;119:396-397. 574. Limperopoulos C, Bassan H, Kalish LA, et al. Current definitions of hypotension do not predict abnormal cranial ultrasound findings in preterm infants. Pediatrics. 2007;120:966-977. 575. Rowe RD, Hoffman T. Transient myocardial ischemia of the newborn infant: a form of severe cardiorespiratory distress in full-term infants. J Pediatr. 1972;81:243-250. 576. Bucciarelli RL, Nelson RM, Egan EA, et al. Transient tricuspid insufficiency of the newborn: a form of myocardial dysfunction in stressed newborns. Pediatrics. 1977;59:330-337. 577. Nelson RM, Bucciarelli RL, Eitzman DV, et al. Serum creatine phosphokinase MB fraction in newborns with transient tricuspid insufficiency. N Engl J Med. 1978;298:146-149. 578. Finley JP, Howman-Giles RB, Gilday DL, et al. Transient myocardial ischemia of the newborn infant demonstrated by thallium myocardial imaging. J Pediatr. 1979;94:263-270. 579. Donnelly WH, Bucciarelli RL, Nelson RM. Ischemic papillary muscle necrosis in stressed newborn infants. J Pediatr. 1980;96: 295-300. 580. Lees MH. Perinatal asphyxia and the myocardium. J Pediatr. 1980;96:675-678. 581. Setzer E, Ermocilla R, Tonkin I, et al. Papillary muscle necrosis in a neonatal autopsy population: incidence and associated clinical manifestations. J Pediatr. 1980;96:289-294. 582. Primhak RA, Jedeikin R, Ellis G, et al. Myocardial ischaemia in asphyxia neonatorum. Electrocardiographic, enzymatic and histological correlations. Acta Paediatr Scand. 1985;74:595-600. 583. van Bel F, Walther FJ. Myocardial dysfunction and cerebral blood flow velocity following birth asphyxia. Acta Paediatr Scand. 1990;79:756-762. 584. Giesinger RE, Bailey LJ, Deshpande P, et al. Hypoxic–ischemic encephalopathy and therapeutic hypothermia: the hemodynamic perspective. J Pediatr. 2017;180:22-30.e22.

Chapter 20  Hypoxic-Ischemic Injury in the Term Infant: Clinical-Neurological Features, Diagnosis, Imaging, Prognosis, Therapy 585. Weindling AM, Bentham J. Commentary on “blood pressure in the neonate”. Acta Paediatr. 2005;94:138-140. 586. Dasgupta SJ, Gill AB. Hypotension in the very low birthweight infant: the old, the new, and the uncertain. Arch Dis Child. 2003;88: F450-F454. 587. Barrington KJ, Dempsey EM. Cardiovascular support in the preterm: treatments in search of indications. J Pediatr. 2006;148: 289-291. 588. Paradisis M, Evans N, Kuckow M, et al. Pilot study of milrinone for low systemic blood flow in very preterm infants. J Pediatr. 2006;148:306-313. 589. Munro MJ, Walker AM, Barfield CP. Hypotensive extremely low birth weight infants have reduced cerebral blood flow. Pediatrics. 2004;114:1591-1596. 590. Noori S, Friedlich P, Wong P, et al. Hemodynamic changes after low-dosage hydrocortisone administration in vasopressor-treated preterm and term neonates. Pediatrics. 2006;118:1456-1466. 591. Kumagai T, Higuchi R, Higa A, et al. Correlation between echocardiographic superior vena cava flow and short-term outcome in infants with asphyxia. Early Hum Dev. 2013;89:307-310. 592. Al Yazidi G, Boudes E, Tan X, et al. Intraventricular hemorrhage in asphyxiated newborns treated with hypothermia: a look into incidence, timing and risk factors. BMC Pediatr. 2015;15:106. 593. Basu P, Som S, Choudhuri N, et al. Contribution of the blood glucose level in perinatal asphyxia. Eur J Pediatr. 2009;168:833-838. 594. Collins JE, Leonard JV. Hyperinsulinism in asphyxiated and small-for-dates infants with hypoglycemia. Lancet. 1984;2:311-313. 595. Azzopardi D, Strohm B, Linsell L, et al. Implementation and conduct of therapeutic hypothermia for perinatal asphyxial encephalopathy in the UK—analysis of national data. PLoS ONE. 2012;7:e38504. 596. Nadeem M, Murray DM, Boylan GB, et al. Early blood glucose profile and neurodevelopmental outcome at two years in neonatal hypoxic-ischaemic encephalopathy. BMC Pediatr. 2011;11:10. 597. Tam EW, Haeusslein LA, Bonifacio SL, et al. Hypoglycemia is associated with increased risk for brain injury and adverse neurodevelopmental outcome in neonates at risk for encephalopathy. J Pediatr. 2012;161:88-93. 598. Inder T. How low can I go? The impact of hypoglycemia on the immature brain. Pediatrics. 2008;122:440-441. 599. Boardman JP, Hawdon JM. Hypoglycaemia and hypoxic-ischaemic encephalopathy. Dev Med Child Neurol. 2015;57(suppl 3):29-33. 600. Cornblath M, Hawdon JM, Williams AF, et al. Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds. Pediatrics. 2000;105:1141-1145. 601. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005;365:663-670. 602. Basu SK, Kaiser JR, Guffey D, et al. Hypoglycaemia and hyperglycaemia are associated with unfavourable outcome in infants with hypoxic ischaemic encephalopathy: a post hoc analysis of the CoolCap Study. Arch Dis Child Fetal Neonatal Ed. 2016;101:F149-F155. 603. Al Shafouri N, Narvey M, Srinivasan G, et al. High glucose variability is associated with poor neurodevelopmental outcomes in neonatal hypoxic ischemic encephalopathy. J Neonatal Perinatal Med. 2015;8:119-124. 604. Basu SK, Salemi JL, Gunn AJ, et al. Hyperglycaemia in infants with hypoxic-ischaemic encephalopathy is associated with improved outcomes after therapeutic hypothermia: a post hoc analysis of the CoolCap Study. Arch Dis Child Fetal Neonatal Ed. 2016;102:F299-F306. 605. Garfinkle J, Shevell MI. Predictors of outcome in term infants with neonatal seizures subsequent to intrapartum asphyxia. J Child Neurol. 2011;26:453-459. 606. Nash KB, Bonifacio SL, Glass HC, et al. Video-EEG monitoring in newborns with hypoxic–ischemic encephalopathy treated with hypothermia. Neurology. 2011;76:556-562. 607. Glass HC, Hong KJ, Rogers EE, et al. Risk factors for epilepsy in children with neonatal encephalopathy. Pediatr Res. 2011;70:535-540. 608. Glass HC, Nash KB, Bonifacio SL, et al. Seizures and magnetic resonance imaging-detected brain injury in newborns cooled for hypoxic–ischemic encephalopathy. J Pediatr. 2011;159:731-735. e731.

563.e13

609. Srinivasakumar P, Zempel J, Trivedi S, et al. Treating EEG seizures in hypoxic ischemic encephalopathy: a randomized controlled trial. Pediatrics. 2015;136:e1302-e1309. 610. Williams CE, Gunn AJ, Mallard C, et al. Outcome after ischemia in the developing sheep brain: an electroencephalographic and histological study. Ann Neurol. 1992;31:14-21. 611. Painter MJ, Pippenger C, MacDonald H, et al. Phenobarbital and diphenylhydantoin levels in neonates with seizures. J Pediatr. 1978;92:315-319. 612. McBride MC, Laroia N, Guillet R. Electrographic seizures in neonates correlate with poor neurodevelopmental outcome. Neurology. 2000;55:506-513. 613. Cataltepe O, Vannucci RC, Heitjan DF, et al. Effect of status epilepticus on hypoxic–ischemic brain damage in the immature rat. Pediatr Res. 1995;38:251-257. 614. Vannucci RC, Connor JR, Mauger DT, et al. Rat model of perinatal hypoxic–ischemic brain damage. J Neurosci Res. 1999;55:158-163. 615. Towfighi J, Housman C, Mauger D, et al. Effect of seizures on cerebral hypoxic–ischemic lesions in immature rats. Brain Res Dev Brain Res. 1999;113:83-95. 616. Myers RE, Williams MV. Lost opportunities for the prevention of fetal asphyxia: sedation, analgesia, and general anaesthesia. Clin Obstet Gynaecol. 1982;9:369-414. 617. Richter JA, Holtman JR Jr. Barbiturates: their in vivo effects and potential biochemical mechanisms. Prog Neurobiol. 1982;18:275-319. 618. Steer CR. Barbiturate therapy in the management of cerebral ischaemia. Dev Med Child Neurol. 1982;24:219-231. 619. Smith AL. Barbiturate protection in cerebral hypoxia. Anesthesiology. 1977;47:285-293. 620. Crane PD, Braun LD, Cornford EM, et al. Dose dependent reduction of glucose utilization by pentobarbital in rat brain. Stroke. 1978;9:12-18. 621. Nilsson L. The influence of barbiturate anaesthesia upon the energy state and upon acid-base parameters of the brain in arterial hypotension and in asphyxia. Acta Neurol Scand. 1971;47:233253. 622. Snyder FF. The effect of pentobarbital sodium upon the resistance to asphyxia in the newborn. Fed Proc. 1946;5:97. 623. Arnfred I, Secher O. Anoxia and barbiturates. Arch Int Pharmacodyn Ther. 1962;139:67. 624. Miller JA, Miller FS. Factors in neonatal resistance to anoxia. Am J Obstet Gynecol. 1962;84:44. 625. Goodlin RC. Drug protection for fetal anoxia. Obstet Gynecol. 1965;26:9. 626. Campbell AG, Milligan JE, Talner NS. The effect of pretreatment with pentobarbital, meperidine, or hyperbaric oxygen on the response to anoxia and resuscitation in newborn rabbits. J Pediatr. 1968;72:518-527. 627. Myers RE. Maternal psychological stress and fetal asphyxia: a study in the monkey. Am J Obstet Gynecol. 1975;122:47-59. 628. Cockburn F, Daniel SS, Dawes GS, et al. The effect of pentobarbital anesthesia on resuscitation and brain damage in fetal rhesus monkeys asphyxiated on delivery. J Pediatr. 1969;75:281-291. 629. Morishima HO, Yeh MN, James LS. Reduced uterine blood flow and fetal hypoxemia with acute maternal stress: experimental observation in the pregnant baboon. Am J Obstet Gynecol. 1979;134:270-275. 630. Fisher DE, Paton JB, Behrman RE. The effect of phenobarbital on asphyxia in the newborn monkey. Pediatr Res. 1975;9:181-184. 631. Eyre JA, Wilkinson AR. Thiopentone induced coma after severe birth asphyxia. Arch Dis Child. 1986;61:1084-1089. 632. Goldberg RN, Moscoso P, Bauer CR, et al. Use of barbiturate therapy in severe perinatal asphyxia: a randomized controlled trial. J Pediatr. 1986;109:851-856. 633. Svenningsen NW, Blennow G, Lindroth M, et al. Brain-orientated intensive care treatment in severe neonatal asphyxia. Effects of phenobarbitone protection. Arch Dis Child. 1982;57:176-183. 634. Hall RT, Hall FK, Daily DK. High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up. J Pediatr. 1998;132:345-348. 635. Meyn DF Jr, Ness J, Ambalavanan N, et al. Prophylactic phenobarbital and whole-body cooling for neonatal hypoxic– ischemic encephalopathy. J Pediatr. 2010;157:334-336.

563.e14

Unit IV  Hypoxic-Ischemic and Related Disorders

636. Dai Y, Tang J, Zhang JH. Role of Cl- in cerebral vascular tone and expression of Na+-K+-2Cl- co-transporter after neonatal hypoxia-ischemia. Can J Physiol Pharmacol. 2005;83:767-773. 637. Pressler RM, Boylan GB, Marlow N, et al. Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial. Lancet Neurol. 2015;14:469-477. 638. Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics. 1998;102:885-892. 639. Azzopardi D, Robertson NJ, Cowan FM, et al. Pilot study of treatment with whole body hypothermia for neonatal encephalopathy. Pediatrics. 2000;106:684-694. 640. Battin MR, Dezoete A, Gunn TR, et al. Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia. Pediatrics. 2001;107:480-484. 641. Battin MR, Penrice J, Gunn TR, et al. Treatment of term infants with head cooling and mild systemic hypothermia (34.5oC) after perinatal asphyxia. Pediatrics. 2003;111:244-251. 642. Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2005;32:11-17. 643. Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: safety outcomes. Pediatr Neurol. 2005;32:18-24. 644. Higgins RD, Raju TN, Perlman J, et al. Hypothermia and perinatal asphyxia: executive summary of the National Institute of Child Health and Human Development workshop. J Pediatr. 2006;148:170-175. 645. Edwards AD, Azzopardi DV. Therapeutic hypothermia following perinatal asphyxia. Arch Dis Child Fetal Neonatal Ed. 2006;91: F127-F131. 646. Wyatt JS, Gluckman PD, Liu PY, et al. Determinants of outcomes after head cooling for neonatal encephalopathy. Pediatrics. 2007; 119:912-921. 647. Azzopardi DV, Strohm B, Edwards AD, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009;361:1349-1358. 648. Laptook AR. The neo.nEURO.network hypothermia randomized controlled trial. Pediatrics. 2010;126:e965-e966. 649. Simbruner G, Mittal RA, Rohlmann F, et al. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. 2010;126:e771-e778. 650. Edwards AD, Brocklehurst P, Gunn AJ, et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ. 2010;340:c363. 651. Jacobs SE, Morley CJ, Inder TE, et al. Whole-body hypothermia for term and near-term newborns with hypoxic–ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med. 2011;165:692-700. 652. Thoresen M. Hypothermia after perinatal asphyxia: selection for treatment and cooling protocol. J Pediatr. 2011;158:e45-e49. 653. Tagin MA, Woolcott CG, Vincer MJ, et al. Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Arch Pediatr Adolesc Med. 2012;166:558-566. 654. Shankaran S, Barnes PD, Hintz SR, et al. Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy. Arch Dis Child. 2012;97:F396-F404. 655. Azzopardi D, Strohm B, Marlow N, et al. Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med. 2014;371:140-149. 656. Zhou WH, Cheng GQ, Shao XM, et al. Selective head cooling with mild systemic hypothermia after neonatal hypoxic–ischemic encephalopathy: a multicenter randomized controlled trial in China. J Pediatr. 2010;157:367-372, 372 e361-e363. 657. Kracer B, Hintz SR, Van Meurs KP, et al. Hypothermia therapy for neonatal hypoxic ischemic encephalopathy in the state of California. J Pediatr. 2014;165:267-273. 658. Massaro AN, Murthy K, Zaniletti I, et al. Short-term outcomes after perinatal hypoxic ischemic encephalopathy: a report from the Children’s Hospitals Neonatal Consortium HIE focus group. J Perinatol. 2015;35:290-296.

659. Dupont TL, Chalak LF, Morriss MC, et al. Short-term outcomes of newborns with perinatal acidemia who are not eligible for systemic hypothermia therapy. J Pediatr. 2013;162:35-41. 660. Lally PJ, Price DL, Pauliah SS, et al. Neonatal encephalopathic cerebral injury in South India assessed by perinatal magnetic resonance biomarkers and early childhood neurodevelopmental outcome. PLoS ONE. 2014;9:e87874. 661. Wassink G, Gunn ER, Drury PP, et al. The mechanisms and treatment of asphyxial encephalopathy. Front Neurosci. 2014;8:40. 662. Thoresen M, Tooley J, Liu X, et al. Time is brain: starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns. Neonatology. 2013;104:228-233. 663. Gerrits LC, Battin MR, Bennet L, et al. Epileptiform activity during rewarming from moderate cerebral hypothermia in the near-term fetal sheep. Pediatr Res. 2005;57:342-346. 664. Wang B, Armstrong JS, Lee JH, et al. Rewarming from therapeutic hypothermia induces cortical neuron apoptosis in a swine model of neonatal hypoxic–ischemic encephalopathy. J Cereb Blood Flow Metab. 2015;35:781-793. 665. Shankaran S, Laptook AR, Pappas A, et al. Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA. 2014;312:2629-2639. 666. Robertson NJ, Marlow N. Depth and duration of cooling for perinatal asphyxial encephalopathy. JAMA. 2014;312:2623-2624. 667. Davidson JO, Wassink G, Yuill CA, et al. How long is too long for cerebral cooling after ischemia in fetal sheep? J Cereb Blood Flow Metab. 2015;35:751-758. 668. Alonso-Alconada D, Broad KD, Bainbridge A, et al. Brain cell death is reduced with cooling by 3.5 degrees C to 5 degrees C but increased with cooling by 8.5 degrees C in a piglet asphyxia model. Stroke. 2015;46:275-278. 669. Silverstein FS, Barks JD. Combining hypothermia with other therapies for neonatal neuroprotection. In: Edwards AD, Azzopardi DV, Gunn AJ, eds. Neonatal Neural Rescue: A Clinical Guide. New York: Cambridge University Press; 2013:208-218. 670. Hobbs C, Thoresen M, Tucker A, et al. Xenon and hypothermia combine additively, offering long-term functional and histopathologic neuroprotection after neonatal hypoxia/ischemia. Stroke. 2008;39:1307-1313. 671. Thoresen M, Hobbs CE, Wood T, et al. Cooling combined with immediate or delayed xenon inhalation provides equivalent longterm neuroprotection after neonatal hypoxia-ischemia. J Cereb Blood Flow Metab. 2009;29:707-714. 672. Dingley J, Tooley J, Liu X, et al. Xenon ventilation during therapeutic hypothermia in neonatal encephalopathy: a feasibility study. Pediatrics. 2014;133:809-818. 673. Azzopardi D, Robertson NJ, Bainbridge A, et al. Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial. Lancet Neurol. 2016;15:145-153. 674. Jatana M, Singh I, Singh AK, et al. Combination of systemic hypothermia and N-acetylcysteine attenuates hypoxic–ischemic brain injury in neonatal rats. Pediatr Res. 2006;59:684-689. 675. van Bel F, Shadid M, Moison RMW, et al. Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics. 1998;101:184-193. 676. Gunes T, Ozturk MA, Koklu E, et al. Effect of allopurinol supplementation on nitric oxide levels in asphyxiated newborns. Pediatr Neurol. 2006;36:17-24. 677. Kaandorp JJ, Benders MJ, Schuit E, et al. Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial. Arch Dis Child Fetal Neonatal Ed. 2015;100:216223. 678. Chaudhari T, McGuire W. Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy. Cochrane Database Syst Rev. 2008;(2):CD006817. 679. Kaandorp JJ, van Bel F, Veen S, et al. Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials. Arch Dis Child Fetal Neonatal Ed. 2012;97:F162-F166.

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