Brain Injury in the Term Infant
Jeffrey M. Perlman, MBChB
Perinatal brain injury in the term infant is a relatively uncommon event. The principal
lesions are intracranial hemorrhage including subarachnoid, subdural, intraparenchymal,
intraventricular, focal cerebral infarction and hypoxic ischemic cerebral injury secondary to
intrapartum hypoxia–ischemia. Both intracranial hemorrhage and focal cerebral infarction
are invariably identified at the time of clinical symptoms, ie, seizures or apnea. This clearly
limits the potential for prevention. The mechanisms contributing to brain injury secondary
to intrapartum hypoxia–ischemia have become more clearly defined. Secondary or reperfusion injury is potentially amenable to neuroprotective strategies. Modest hypothermia is
one such therapy that has been studied in high-risk newborn infants with some initial
success. Future studies need to focus on additional neuroprotective strategies.
Semin Perinatol 28:415-424 © 2004 Elsevier Inc. All rights reserved.
P
erinatal brain injury that occurs in the term infant is
relatively uncommon affecting approximately 1 per
1000 live births, and is most often secondary to hemorrhage, focal cerebral infarction and hypoxia–ischemia
cerebral injury.1 Much less frequent causes of injury include metabolic disturbances related to inborn errors of
metabolism, hypoglycemia, hyperbilirubinemia and infection/meningitis (Table 1). The clinical expression of neonatal brain injury may range from subtle, ie, mild hypotonia or a hyperalert state to severe, ie, stupor or coma. The
short- and long-term consequences will depend on the
severity and extent of the underlying pathologic process.
Many of the causes of perinatal brain injury are only identified at the time of clinical symptoms, limiting the potential for prevention.2 Recent advances in the understanding
of the genesis of brain injury secondary to hypoxia–ischemia have facilitated the introduction of neuroprotective
strategies that may prevent ongoing injury. This chapter
will deal with intracranial hemorrhage, focal cerebral infarction and brain injury secondary to intrapartum hypoxia–ischemia in terms of etiology, clinical manifestations, diagnosis, and in addition focus on potential
neuroprotective strategies following intrapartum hypoxia–ischemia.
Division of Neonatology, Department of Pediatrics, Joan and Sanford I. Weill
Medical College and Graduate School of Medical Sciences at Cornell
University, New York, NY.
Address reprint requests to: Jeffrey M. Perlman, MBChB, New York Presbyterian Hospital, Joan and Sanford I. Weill Medical College and Graduate
School of Medical Sciences of Cornell University, Department of Pediatrics, Division of Neonatology, 525 East 68th Street, Box 106, New York,
NY 10021. E-mail: jmp2007@med.cornell.edu
0146-0005/04/$-see front matter © 2004 Elsevier Inc. All rights reserved.
doi:10.1053/j.semperi.2004.10.003
Intracranial Hemorrhage
Intracranial hemorrhage remains an important problem in
the term infant. The hemorrhage may be confined to the
extracranial space, ie, subarachnoid, subdural and epidural
or evolve within the brain parenchyma and/or ventricular
system. Although trauma has often been credited with causing most hemorrhagic lesions in term infants, it is likely that
other factors are involved in many of these cases.1 Indeed the
incidence of intracranial hemorrhage attributed to “trauma”
appears to be declining. This may reflect both an improvement in perinatal care and the increasing recognition that
some of the lesions once attributed to trauma may be unrelated to the delivery process. Thus, the occurrence of in utero
subdural hemorrhage has been documented with increasing
frequency following the wider use of prenatal ultrasonography.3,4 Of the various types of intracranial hemorrhage, subarachnoid hemorrhage is the most common followed by subdural hematoma with epidural hemorrhage being extremely
uncommon.1 The cerebral convexities and the temporal fossa
are the most likely sites of bleeding, but hemorrhage adjacent
to the flax, the tentorium, or the posterior fossa also occurs.
Subarachnoid Hemorrhage
Subarachnoid hemorrhage (SAH) can be categorized as either
primary or secondary in origin. Primary SAH refers to hemorrhage in the subarachnoid space that is not secondary to
extension from a subdural, intraventricular, or intracerebellar hemorrhage. It is the most common form of intracranial
bleeding in term neonates.1 Bleeding most frequently results
from rupture of small veins bridging the leptomeninges. Secondary SAH is due to extension of subdural, intraventricular,
415
J.M. Perlman
416
Table 1 Causes of Perinatal Brain Injury in the Term Infant
Intracranial Hemorrhage
Primary subarachnoid hemorrhage
Subdural hematoma
Epidural hematoma
Intracerebral hemorrhage
Thalamic hemorrhage
Intraparenchymal hemorrhage
Intraventricular hemorrhage
Germinal matrix hemorrhage
Focal Cerebral Infarction
Hypoxic Ischemic Cerebral Injury
Vascular abnormalities
Aneurysm
Arteriovenous malformation
Metabolic Disorders
Inborn errors of metabolism (eg, hyerpammonemia)
Hypoglycemia
Hyperbilirubinemia
Cerebral Tumors
Idiopathic
or intraparenchymal hemorrhages and occurs less often.
While “trauma” is by far the most common etiology of SAH in
term neonates, coagulation disorders and rupture of an intracranial aneurysm or arteriovenous malformation are occasionally responsible. However small SAH is probably frequent even during uncomplicated deliveries, but cause little
or no problems and thus goes unrecognized. The most common clinical presentation is seizures, whose onset is on approximately on the second postnatal day. In the interictal
period, the infants appear remarkable well. A second presentation is that of recurrent apnea, whose onset may be in the
first 24 hours of life. Rarely, a third presentation is that of
more extensive bleeding into the cerebrospinal fluid causing
seizures, a bulging anterior fontanel or diminished responsiveness.
Subdural Hemorrhage
Subdural hematoma (SDH) can be categorized into two main
groupings according to their origin and direction of spread,
ie, supratentorial and infratentorial5 Significant hemorrhage
may result from tears in the falx and tentorium or bridging
cortical veins secondary to stretching, which is most likely to
occur during labor, under circumstances when anterior–posterior compression of the head is associated with excessive
vertical molding and frontal– occipital elongation of the cranium.1 Thus SDH has long been considered a traumatic lesion related to difficult parturition. However as noted previously there are several case reports documenting antenatal
sudural hematoma.3,4 Moreover SDH has also been documented after spontaneous vaginal delivery.6,7
The clinical expression varies depending on the size and
location of the blood. Thus small hemorrhages adjacent to
the cerebrum usually cause no major difficulty.6,7 However,
depending on location, in particular within the posterior
fossa, even small amounts of blood, sometimes result in ob-
structive hydrocephalus or striking neurological deficit.
Large acute SDH are apt to produce signs of increased intracranial pressure, seizures, and focal neurological deficits.
Very large SDH adjacent to the cerebral hemispheres may
lead to herniation of the temporal lobe over the tentorial
edge, causing ipsilateral third nerve paralysis.6,7 Additional
signs with large lesions include a paucity of spontaneous
movement, decreased responsiveness as well as nonspecific
signs such as metabolic acidosis, hypoglycemia, anemia and
hypotension.8,9 Most neonates with a catastrophic syndrome
do not survive, and the few who do are usually left with
severe neurological sequelae. Chronic subdurals over the
convexity usually present with macrocephaly, seizures, or
failure to thrive.
Epidural Hemorrhage
Epidural hemorrhage is a rare lesion in the neonate, accounting for approximately 2% of all cases of neonatal intracranial
hemorrhage observed at autopsy.9 Bleeding is derived from
branches of the middle meningeal artery or from major veins
or venous sinuses. Possible explanations for the infrequent
occurrence are: (1) the loose attachment of the meningeal
vessels to the overlying bone, which allows the neonate to
withstand more trauma to the skull without lacerating the
vessel underneath; and (2) the dura which is unusually thick
and largely continuous with the inner periosteum. The skull
it self is more pliable in infants, and thus less likely to fracture. Progressive neurological dysfunction and death commonly result unless the epidural hemorrhage is evacuated
and further bleeding stopped.
Diagnosis
The diagnosis of subdural, epidural, or subarachnoid hemorrhage is confirmed by computed tomography, which outlines both the location and extent of bleeding in most cases.
However, magnetic resonance imaging is more effective than
computed tomography in the delineation of posterior fossa
hemorrhages.7 Skull radiographs may demonstrate fracture
or suture separation, but are not of much help clinically since
hematomas are often present without these lesions. Cranial
ultrasound scanning is less useful in establishing a diagnosis
due the peripheral location of convexity subdural or epidural
hemorrhages that limits their visualization. Both cranial ultrasound imaging and computed tomography and more recently magnetic resonance imaging, effectively outline the
hydrocephalus that sometimes accompanies intracranial
bleeding.
Treatment
Early diagnosis of intracranial hemorrhage is imperative,
since the outcome so often depends on prompt therapy.
Large acute subdural and epidural hemorrhages should be
surgically evacuated and any source of continued bleeding
ligated. Emergency craniotomy is particularly important with
tentorial tears extending into the dural sinuses. Decompres-
Brain injury in the term infant
sion should also be considered for larger intracerebellar hematomas. Smaller subdural or epidural lesions in a stable
child will frequently resolve without surgery. No specific
treatment is available for acute subarachnoid hemorrhage in
neonates, though close follow-up for signs of hydrocephalus
is recommended.
Prognosis
The prognosis following hemorrhage is variable, depending
on the size and location of the lesion, the promptness of
treatment, and whether underlying brain damage was coincident to the hemorrhage. Epilepsy, mental retardation, motor deficits, or other sequelae may result from intracranial
hemorrhage regardless of its site or etiology. In general, the
prognosis after subdural hematomas is better in infants than
in older children. The outlook for convexity subdural hematoma is often favorable, while the prognosis of patients with
posterior fossa subdural hemorrhage is less encouraging.
Without surgery, rapid deterioration of brain stem function
followed by cardio respiratory failure is typical of these posterior fossa lesions, although occasional patients do well. Isolated subarachnoid and intraventricular hemorrhage may
lead to hydrocephalus long after the hemorrhage, but surviving patients otherwise tend to recover fully.
Intracerebral Hemorrhage
Intracerebral hemorrhage in the term infant is uncommon.
Blood may be found within the germinal matrix, ventricles or
brain parenchyma. The thalamus appears to be a common
site of hemorrhage in the term infant and frequently includes
intraventricular hemorrhage as well.10,11 Typically the hemorrhage develops later, ie, during the second week of life, but
it may occur earlier. Predisposing factors include prior hypoxic–ischemic cerebral injury, sepsis, and coagulopathy or
may be observed in association with subarachnoid or subdural hemorrhage.7,8 Primary intraventricular hemorrhage is
rare in the term infant. Documented sources of hemorrhage
in this age group include residual germinal matrix, choroids
plexus and thalamus. Predisposing factors include prior hypoxia–ischemia, coagulopathies and arteriovenous malformations.
The clinical presentation of intracerebral hemorrhage is
characterized by sudden onset of marked neurologic abnormalities, including signs of seizures, evidence of increased
intracranial pressure and downward eye deviation. A bulging
fontanel or blood in the cerebrospinal fluid may be present.
Hemiparesis or other focal neurological deficits are uncommon. Neuroimaging, ie, cranial ultrasound, CT or MRI
readily establishes the diagnosis. The prognosis is surprisingly good with primary thalamic hemorrhage although
when associated with intraventricular hemorrhage, outcome
is less favorable.10,11
Cerebral Infarction
Cerebral infarction in the neonate, ie, perinatal stroke is a
more common than has been considered in the past with an
417
estimate of 1 in 4000 births.12,13 The infarction may arise
from both embolic and thrombotic phenomena, however the
etiology in most cases remains unclear.12-14 Cerebral embolism is probably the most common cause of stroke in this
setting, though the site of origin for the embolism is not
always apparent. Other reported causes include intrapartum
“asphyxia,” deficiency of one of the systemic coagulation inhibitors (ie, protein C or protein S), primary hemorrhage
with vasospasm, meningitis, polycythemia, extracorporeal
membrane oxygenation, etc.15-19 The initial clinical manifestations typically consist of seizures or apnea, usually on the
second postnatal day. Focal deficits are not common except
with large deficits. The diagnosis may be established by cranial ultrasonography, CT or MRI.19 The outcome depends on
the location and the extent of the lesion. Involvement of the
thalamus is invariably associated with contralateral hemiplegia. Smaller lesions may allow a normal outcome.20
Cerebral Injury Secondary to
Intrapartum Hypoxia–Ischemia
Hypoxic ischemic cerebral injury that occurs during the perinatal period is one of the most commonly recognized causes
of severe, long-term neurological deficits in children, often
referred to as cerebral palsy (CP).1,2 The brain injury that
develops is an evolving process initiated during the insult and
extends into a recovery period, the latter referred to as the
“reperfusion phase” of injury. It is during this phase of injury
that intervention strategies maybe possible.21 In this section,
the pathogenesis, early identification of high-risk infants as
potential candidates for neuroprotective strategies and some
future interventions following intrapartum hypoxia–ischemia will be briefly reviewed.
Pathogenesis
The principal pathogenetic mechanism underlying most of
the neuropathology attributed to intrapartum hypoxia–ischemia is impaired cerebral blood flow (CBF). This is most
likely to occur as a consequence of interruption in placental
blood flow and gas exchange, often referred to as “asphyxia”
or severe fetal acidemia. The latter is defined as a fetal umbilical arterial pH ⱕ 7.00.2 At the cellular level, the reduction in
cerebral blood flow and oxygen delivery initiates a cascade of
deleterious biochemical events. Depletion of oxygen precludes oxidative phosphorylation, and results in a switch to
anaerobic metabolism. This is an energy inefficient state resulting in rapid depletion of high-energy phosphate reserves
including ATP, accumulation of lactic acid and the inability
to maintain cellular functions.22 Transcellular ion pump failure results in the intracellular accumulation of Na⫹, Ca2⫹ and
water (cytotoxic edema). The membrane depolarization results in a release of excitatory neurotransmitters and specifically glutamate from axon terminals. Glutamate then activates specific cell surface receptors resulting in an influx of
Na⫹ and Ca2⫹ into postsynaptic neurons. Within the cytoplasm, there is an accumulation of free fatty acids secondary
J.M. Perlman
418
to increased membrane phospholipid turnover. The fatty acids undergo per oxidation by oxygen free radicals that arise
from reductive processes within mitochondria and as byproducts in the synthesis of prostaglandins, xanthine and
uric acid. Ca2⫹ ions accumulate within the cytoplasm as a
consequence of increased cellular influx as well as decreased
efflux across the plasma membrane combined with release
from mitochondria and endoplasmic reticulum. In selected
neurons, the intracellular calcium induces the production of
nitric oxide, a free radical that diffuses to adjacent cells susceptible to nitric oxide toxicity. The combined effects of cellular energy failure, acidosis, glutamate release, intracellular
Ca2⫹ accumulation, lipid per oxidation and nitric oxide neurotoxicity serve to disrupt essential components of the cell
with its ultimate death.1,23 Many factors including the duration or severity of the insult will influence the progression of
cellular injury following hypoxia–ischemia.
Delayed (Secondary) Brain Injury
Following resuscitation, which may occur in utero or postnatally in the delivery room, cerebral oxygenation and perfusion is restored. During this recovery phase, the concentrations of phosphorus metabolites and the intracellular pH
return to baseline. However, the process of cerebral energy
failure recurs from 6 to 48 hours later in a second phase of
injury. This phase is characterized by a decrease in the ratio of
phosphocreatine/inorganic phosphate, with an unchanged
intracellular pH, stable cardio respiratory status, and contributes to further brain injury.22,24 In the human infant the severity of the second energy failure is correlated with adverse
neurodevelopment outcome at 1 and 4 years.25 The mechanisms of secondary energy failure may involve mitochondrial
dysfunction secondary to extended reactions from primary
insults (eg, calcium influx, excitatory neurotoxicity, oxygen
free radicals or nitric oxide formation). Indeed mitochondria
play a key role in determining the fate of neurons following
hypoxia–ischemia. Thus translocation of apoptotic triggering
proteins such as cytochrome c from the mitochondria to the
cytoplasm can activate a cascade of proteolytic enzymes
termed caspases or cysteine proteases that eventually trigger
nuclear fragmentation.23 Recent evidence also suggests that
circulatory and endogenous inflammatory cells/mediators
also contribute to ongoing brain injury.26 The potential role
of inflammation is discussed in greater detail next.
Inflammatory Mediators
Inflammatory mediators appear to play a critical role in the
pathogenesis of hypoxic ischemic brain injury. Thus expression of IL-1- ␤ and TNF ␣ mRNA has been demonstrated
within 1 to 4 hours following hypoxia ischemia,27 along with
the induction of ␣ and ␤ chemokines followed by neutrophil
invasion of the area of infarction.28 Furthermore a low dose of
bacterial endotoxin administered four hours before hypoxia–
ischemia in rats, induces cerebral infarction in response to
short periods of hypoxia–ischemia that usually causes little or
no injury. This endotoxin-induced sensitization of the imma-
ture brain occurs independent of cerebral blood flow changes
and/or hyperthermia and is associated with an altered expression of CD14 mRNA.29 Inflammatory cytokines may have a
direct toxic effect via increased production of inducible nitric
oxide synthase, cyclo-oxygenase and free radical release, or
indirectly via induction of glial cells to produce neurotoxic
factors such as excitatory amino acids. The important role of
cytokines in perpetuating excitotoxic injury is suggested
from experimental observations in which administration of
IL-1 endogenous receptor antagonists as well as neutralizing
antibody are associated with a reduction in excitotoxic and
ischemic injury in mice.30,31 However, cytokines that potentiate brain damage following ischemia also seem to play a
beneficial neurotrophic effect. Thus TNF knockout mice
were shown to have increased neuronal cell degeneration
following ischemia and excitotoxic injury suggesting a critical role for endogenous TNF in regulating the cellular responses to brain injury.32 In addition administration of exogenous IL-6 following ischemia produced by middle artery
occlusion also results in marked neuroprotection.33 Thus inflammatory cytokines appear to exert both beneficial and
deleterious effects following ischemia. This dual effect will
likely complicate the task of developing targeted interventions against the inflammatory response.
Mechanisms
of Neuronal Death
Following Hypoxia–Ischemia
The mechanism of neuronal cell death in animals and human
following hypoxia–ischemia includes neuronal necrosis and
apoptosis. The intensity of the initial insult may determine
the mode of death with severe injury resulting in necrosis,
while milder insults result in apoptosis.34 Necrosis is a passive process of cell swelling, disrupted cytoplasmic organelles, loss of membrane integrity and eventual lyses of
neuronal cells and activation of an inflammatory process. By
contrast, apoptosis is an active process distinguished from
necrosis by the presence of cell shrinkage, nuclear pyknosis,
chromatin condensation and genomic fragmentation, events
that occur in the absence of an inflammatory response.35
These two processes of neuronal death can be demonstrated
following hypoxia ischemia in both animals and humans.1,23,35 Since the mechanisms of neuronal necrosis versus apoptosis likely differ (see above), strategies to minimize
brain damage in an affected infant following hypoxia–ischemia likely will have to include interventions that target both
processes.
Clinical Manifestations
Clinical findings will vary depending on the timing of the
intrapartum insult, the duration of the insult and fetal adaptive mechanisms.1,2 Commonly the infant will initially appear
clinically depressed, ie, lethargic with central hypotonia, particularly proximally (likely related to reduced parasagittal
blood flow) and with reduced deep tendon reflexes. Over the
Brain injury in the term infant
next several hours there is in most cases an improvement in
the clinical status with an improvement in the level of responsiveness. Indeed in some infants there is an appearance of a
hyperalert state. The hypotonia generally tends to persist and
the reflexes are now easily elicited. In some there maybe
sensory stimulus clonus. Clinical seizures if present are usually noted between 12 and 24 hours of postnatal age. The
subsequent clinical course may range from a hyperalert state
with rapid recovery and no seizures (the most common presentation), a state designated as Sarnat Stage 1 encephalopathy,36 to seizures with moderate encephalopathy characterized by lethargy, a state designated Sarnat Stage 2
encephalopathy, and finally with progression to severe encephalopathy characterized by stupor or coma, loss of brainstem signs, loss of deep tendon reflexes, absence of clinical ⫾
electrographic seizures a state designated Sarnat Stage 3 encephalopathy. The clinical findings usually evolve over the
first 24 to 72 hours of postnatal life. There are a small number
of infants who will present and maintain a severe encephalopathic state from birth. The outcome following intrapartum
hypoxia–ischemia is strongly related to the severity of the
clinical examination. Thus almost all infant with stage 1 encephalopathy develop normally, approximately 75 to 80% of
infants with stage 2 encephalopathy develop normally,
whereas no infants with stage 3 encephalopathy develops
normally.1 Indeed the outcome is dismal in all cases. The
extent of damage and likely outcome can be supported with
an electroencephalogram (EEG) (the appearance of a burst
suppression pattern is associated with a poor prognosis), and
magnetic resonance imaging (see below). The recognition
and importance of reperfusion injury, and the potential to
implement neuroprotective strategies and thus reduce neurologic morbidity has led to an earlier identification of high
risk infants with a modified Sarnat scoring system and use of
a modified EEG (see subsequent section on treatment).
Detection of Neuronal
Injury with Magnetic
Resonance (MR) Imaging
MR techniques have become very important in delineating
evolving structural, metabolic and functional changes following intrapartum hypoxia–ischemia.37 Thus using conventional MR, three patterns of signal abnormalities can be identified including injury to the thalami and/or posterior–lateral
putamen with involvement of the subcortical white matter in
the most severe cases; injury to the parasagittal gray matter
and subcortical white matter, posteriorly usually more than
anteriorly; and focal or multifocal injury.38 Conventional MR
studies are of limited value in the early phases, ie, hours and
days following the insult. More recently the use of advanced
MR techniques, ie, diffusion weighted imaging (DWI) has
been utilized to detect early injury.39 This technique measures the self-diffusion of water detected as an apparent diffusion coefficient (ADC).37 Thus the ADC decreases with
acute injury and is reflective of reduced water diffusivity in
the tissue. Studies of adult arterial infarcts have shown that
419
DWI signal changes occur within minutes of symptom onset
and hours before changes become apparent on T1- or T2weighted images.40 This earlier detection of injury may facilitate intervention before irreversible injury. DWI changes
may be negative if it is performed earlier than 24 hours of life
or later than 8 days of life.37 Recently the development of
magnetic resonance spectroscopy (MRS) has facilitated the
detection of tissue metabolism and in vivo biochemistry.37,38
Thus proton MRS (1H-MRS) can identify a spectrum of metabolites including lactate, creatine, N-acetylaspartate (NAA)
and glutamine to name a few. Indeed elevated lactate levels
have been demonstrated following hypoxia–ischemia in 1HMRS with regional differences, ie, higher lactate/NAA ratios
in basal ganglia than in occipito-parietal cortex.41 Moreover
an early elevated lactate/creatine ratio with 1H-MRS coupled
with a low phosphocreatine/inorganic phosphate ratio done
with phosphorus MRS correlated with neurodevelopmental
outcome at 1 year.42 Thus the data indicate that MRS plays an
important role in the assessment of the encephalopathic infant following intrapartum hypoxia–ischemia.
Management
The goals of management of a newborn infant who has sustained a hypoxic–ischemic insult and is at risk for evolving
injury should include: (1) early identification of the infant at
highest risk for evolving injury, (2) supportive care to facilitate adequate perfusion and nutrients to the brain, and (3)
consideration of interventions to ameliorate the processes of
ongoing brain injury. Each of these approaches is briefly
discussed next.
Early Identification
of High Risk Infants
The initial step in management is early identification of those
infants at greatest risk for evolving to the syndrome of hypoxic–ischemic encephalopathy (HIE). This is a highly relevant issue because the therapeutic window, ie, the time
interval following hypoxia–ischemia during which interventions might be efficacious in reducing the severity of ultimate
brain injury, is likely to be short. Based on experimental
studies it is estimated to vary from 2 to 6 hours. Given this
presumed short window of opportunity, infants must be
identified as soon as possible following delivery to facilitate
the implementation of early interventions. There are increasing data to indicate that the highest risk infant can be identified shortly after birth by a constellation of findings. These
include evidence of a sentinel event during labor, ie, fetal
heart rate abnormality, a severely depressed infant (low extended Apgar score), the need for resuscitation in the delivery
room (ie, intubations, chest compression ⫾ epinephrine administration), evidence of severe fetal acidemia (cord umbilical artery pH ⬍ 7.00 and/or base deficit ⬎ ⫺16 mEq/L),43
followed by evidence of an early abnormal neurologic examination and/or abnormal assessment of cerebral function, ie,
integrated EEG.44-46 Thus in a prospective study of 50 infants
J.M. Perlman
420
Table 2 A Guide to the Supportive Management of an Infant at
Risk for Hypoxic Ischemic Cerebral Injury
Ventilation
Maintain paCO2 within a normal range
Perfusion
Promptly treat hypotension
Avoid hypertension
Fluid status
Initial fluid restriction
Follow serum sodium and daily weights
Blood glucose
Maintain blood glucose within a normal range
Avoid hypoglycemia
Seizures
Treat clinical seizures, particularly with an
electrographic correlate
Potential role of prophylactic phenobarbital
Electrolyte imbalance
Monitor serum electrolytes, calcium and magnesium
who had evidence of intrapartum distress, Apgar score 5 at 5
minutes, or cord arterial pH 7.00 and underwent an early
neurologic examination using a modified Sarnat staging system (stages 2 and 3 were regarded as abnormal) and a blinded
simultaneous a-EEG measurement, predictive values were
calculated for a short-term abnormal outcome defined as persistent moderate to severe encephalopathy beyond 5 days. An
abnormal outcome evolved in 14 (28%) of the 50 infants. The
neurologic examination was performed at 5 ⫾ 3 hours after
delivery. A short-term abnormal outcome occurred in 9
(53%) of 17 infants with initial stage 2 and in both infants
with initial stage 3 encephalopathy. In addition, 13 infants
manifested features of both stage 1 and 2 encephalopathy and
post hoc were classified (S1–2). Three of the latter infants
(23%) developed an abnormal short-term outcome. The aEEG was abnormal in 15 (30%) infants, 11 (73%) of whom
developed an abnormal outcome. An abnormal a-EEG was
more specific (89% versus 78%), had a greater positive predictive value (73% versus 58%), and had similar sensitivity
(79% versus 78%) and negative predictive value (90% versus
91%) when compared with an abnormal early neurologic
examination. A combination of abnormalities had the highest
specificity (94%) and positive predictive value (85%). Thus a
combination of the a-EEG and the neurologic examination
shortly after birth enhances the ability to identify high-risk
infants and limits the number of infants who would be falsely
identified compared with either evaluation alone.46
Supportive Care
Supportive care should be directed toward the maintenance
of adequate ventilation (avoid hyper and hypocarbia), avoidance of hypotension, judicious fluid management, avoidance
of hypoglycemia and the treatment of seizures21 (Table 2).
For the purposes of this review, the importance of seizures as
a cause of ongoing injury and the potential role of prophylactic phenobarbital is briefly discussed next.
Seizures as a
Cause of Ongoing Injury
Although seizures are a consequence of the underlying brain
injury, ie, hypoxia–ischemia, seizures activity in itself may
contribute to ongoing injury. Experimental evidence strongly
suggests that repetitive seizures disturb brain growth and
development as well as increase the risk for subsequent epilepsy.47,48 Despite the potential adverse effects of seizures, the
question of which infants should be treated remains controversial.1,49 This is in part related to the observation that not all
clinical seizures have an electrographic correlation.50
Prophylactic Phenobarbital
Experimental data indicates that barbiturate pretreatment
and even early post treatment in adult animals subjected to
cerebral hypoxia–ischemia reduces the severity of ultimate
brain damage. The prophylactic administration of “high
dose” barbiturates to infants at highest risk for evolving to
HIE has been evaluated in two small studies with conflicting
results.51,52 In the first randomized study, the administration
of Thiopental initiated within two hours and infused for 24
hours did not alter the frequency of seizures, intracranial
pressure or short-term neurodevelopmental outcome at 12
months.51 Of importance was the observation that systemic
hypotension occurred significantly more often in the treated
group. In the second randomized study, Phenobarbital 40
mg/kg body weight administered intravenously between 1
and 6 hours to asphyxiated infants was associated with subsequent neuroprotection.52 Although there was no difference
in the frequency of seizures between the two groups in the
neonatal period, 73% of the pretreated infants compared
with 18% of the control group (P ⬍ 0.05) revealed normal
neurodevelopmental outcome at 3-year follow-up. No adverse effect of phenobarbital administration was observed in
this study. Thus, the role of prophylactic barbiturates in
high-risk infants remains unclear at this current time and
may be worthy of further investigation.
Potential Neuroprotective
Strategies Aimed at
Ameliorating Secondary
Brain Injury
Hypothermia
Modest systemic or selective cooling of the brain by as little as
2-4°C has been shown to reduce the extent of tissue injury in
experimental studies as well as human following events such
as stroke, trauma or cardiac arrest.53-68 Potential mechanisms
of neuroprotection with hypothermia include inhibition of
glutamate release, reduction of cerebral metabolism which in
turn preserves high energy phosphates, decrease in intracellular acidosis and lactic acid accumulation, preservation of
endogenous antioxidants, reduction of nitric oxide production, prevention of protein kinase inhibition, improvement of
Brain injury in the term infant
protein synthesis, reduction of leukotriene production, prevention of blood brain barrier disruption and brain edema
and inhibition of apoptosis.64,66 Although neuroprotection
following intraischemic hypothermia is well established, the
effects of postischemic hypothermia have been less certain.
The latter is the typical scenario in the human newborn.
Before initiating hypothermia as a therapeutic strategy in neonates, several factors had to be considered. The first relates
to duration of therapy. Thus, brief postischemic hypothermia, ie, less than 6 hours results is only partial or temporary
neuroprotection in most experimental animals.53,66 Prolonging postischemic hypothermia from 24 to 72 hours attenuates brain damage and improves behavioral performance.57,58,66 The second factor relates to the degree of
hypothermia. Accordingly, moderate hypothermia at brain
temperatures of 32 to 34°C initiated immediately or within a
few hours after reperfusion and continued for 24 to 72 hours
has been shown to favorably affect outcome in adult and
newborn animals.57,58 The third factor relates to the delay in
initiation of therapy. Clearly, the sooner hypothermia can be
initiated, the more likely it is to be successful. Indeed studies
indicate that if therapy is initiated beyond 6 hours following
hypoxia–ischemia or following the onset of seizures, that
hypothermia is not neuroprotective.59,60 The fourth factor
relates to the method of achieving hypothermia. Selective
head cooling is attractive because it reduces potential side
effects (see below) but is associated with differential gradients
within the brain.69 Total body cooling is more likely to be
associated with side effects but less temperature gradient
within the brain. A major concern of hypothermia in newborn infants relates to potential adverse effects including
hypoglycemia, reduction of myocardial contractility and ventilation–perfusion mismatch, increased blood viscosity, acidbase and electrolyte imbalance and an increased risk of infection.65,70
To address the practicality and safety of mild or minimal
hypothermia, pilot studies were conducted utilizing both selective and systemic methods to cool the brain in term neonates with moderate to severe encephalopathy.71,72 Subsequently two large randomized multicenter studies have been
undertaken and completed in term infants at highest risk for
evolving to moderate and/or severe encephalopathy, using
either selective or systemic modest hypothermia. One of
these studies utilizing selective head cooling has reported
follow up results at 18 months (A. Gunn, personal communication). There was no overall protective effect of hypothermia observed with regard to the development of cerebral
palsy and/or death. However for those infants who presented
with moderate encephalopathy and without electrographic
seizures, a significant benefit of hypothermia was noted.
Conversely no effect was observed in those infants with severe encephalopathy and/or early seizures. As a consequence
of these preliminary data several key questions need further
delineation: (1) What is the ideal temperature for selective
head cooling? (2) Which is the best mode of inducing hypothermia, ie, selective head versus total body cooling? (3) How
long should hypothermia be maintained? (4) Will a multimo-
421
dal approach especially for the more severely affected infants
be more effective than hypothermia alone?
Oxygen Free Radical
Inhibitors and Scavengers
Since oxygen free radicals are considered important in the
genesis of ongoing injury following hypoxia–ischemia, therapies targeted at the destruction of oxygen free radicals have
been developed. Such strategies include the administration of
specific antioxidant enzymes, ie, superoxide dismutase and
catalase known to degrade highly reactive radicals to a nonreactive component. In newborn animals, neuroprotection
has only been shown when these agents have been administered several hours before the hypoxic–ischemic insult.21,73
Specific free radical inhibition of xanthine production, ie,
with allopurinol and oxypurinol (xanthine oxidase inhibitors) protects the immature rat from hypoxic–ischemic brain
damage when the drugs are administered early during the
recovery phase following resuscitation.21 In a recent clinical
study, allopurinol administered to asphyxiated infants reduced blood concentrations of oxygen free radicals when
compared with control infants.74 A third approach of free
radical inhibition has targeted the formation of free radicals
specifically hydroxyl radical from free iron during reperfusion.26 Thus, desferoxamine, a chelating agent, prevents the
formation of free radical from iron, reduces the severity of
brain injury and improves cerebral metabolism in animal
models of hypoxia–ischemia when given during reperfusion.26,75
Excitatory Amino Acid Antagonists
Given the important role of excessive stimulation of neuronal
surface receptors by glutamate in promoting a cascade of
events leading to cellular death,1,23 it has been logical to identify pharmacological agents that would either inhibit glutamate release or block its postsynaptic action. Glutamate receptor antagonists (ie, NMDA, AMPA subtypes) have been
extensively investigated in experimental animals. Noncompetitive antagonists provided a reduction in brain damage in
adult animals even when administered up to 24 hours after
the insult. Available NMDA antagonists include dizocilpine
(MK-801), magnesium, phencyclidine (PCP), dextrometrophan and ketamine.21 Relevant to the neonate, magnesium is
an NMDA antagonist blocking neuronal influx of Ca2⫹ within
the ion channel. Magnesium sulfate is an attractive agent
because of its frequent use in the United States. It is often
administered to mothers for tocolysis or to prevent seizures
in mothers with pregnancy-induced hypertension. In developing brain, the potential effect of magnesium appears to be
dependent on the maturation of the glutamate receptor system. Thus, in mice, excitotoxic neuronal death was limited
by magnesium which was effective only after development of
several aspects of the excitotoxic cascade, including the coupling of the calcium influx following NMDA over stimulation, and the presence of magnesium-dependent calcium
channels.76 Additional experimental studies have revealed
conflicting data. Thus, when administered shortly following
J.M. Perlman
422
an intracerebral injection of NMDA, magnesium sulfate reduced brain injury in newborn rats. By contrast in a piglet
model of asphyxia, magnesium sulfate administered 1 hour
following resuscitation failed to decrease the severity of delayed energy failure. In addition, in a near-term fetal lamb
model, magnesium sulfate administered before and during
umbilical cord occlusion did not influence the electrophysiological responses or neuronal loss.21,77,78 Preliminary retrospective observations in premature infants note a reduced
incidence of CP at 3 years in those exposed to antenatal
magnesium sulfate79 A small randomized clinical study
showed some subtle benefits, ie, on CT imaging and clinically
as indicated by improved feeding at 14 days from magnesium
infusion.80 Clearly, future research is necessary to determine
the potential neuroprotective role of magnesium.
Prevention of
Nitric Oxide Formation
The experimental effects of NOS inhibitors vary and are animal species specific and influenced by the pharmacological
agent used, the dose and timing of therapy. Thus, in adult
experiments, the severity of neuronal loss can be reduced by
the prior administration of inhibitors of NOS activity. Although a similar protective effect has been observed in the
immature rat, in fetal sheep, neuronal injury appears to be
accentuated following hypoxia–ischemia.21
Calcium Channel Blockers
The elevation of cytosolic calcium during and following hypoxic–ischemic injury makes the reduction of intracellular
accumulation a highly desirable therapy. The use of calcium
channel blockers, eg, flunarizine, has been studied in fetal
and newborn animals and the neuroprotective effect has only
been demonstrated when given before but not following hypoxic–ischemia.21 In a pilot study, nicardipine was tested in
four severely asphyxiated infants but the positive effect was
counteracted by the adverse effects of significant hemodynamic disturbance.81 Indeed, current calcium channel blocks
are in general contraindicated in the neonate and young infant in the United States because of significant adverse cardiovascular effects.
Other Potential
Neuroprotective Avenues
Other avenues of potential neuroprotection include platelet-activating factor antagonists,82 adenosinergic agents,83 monosialoganglioside GM1,84 growth factors, eg, nerve growth factor
(NGF),85 insulin growth factor-186 and blocking the apoptotic
pathways, ie, minocycline,87 erythropoeitin, etc.88,89
Summary
Much progress has been made toward understanding the
mechanisms contributing to ongoing brain injury following
hypoxia–ischemia. This should facilitate more specific pharmacologic intervention strategies that might provide neuroprotection during the reperfusion phase of injury. Early identification of infants at highest risk for brain injury is critical if
such interventions are to be successful.
Conclusions
Perinatal brain injury resulting in long-term neurodevelopmental deficits occurs most often as a consequence of intrapartum hypoxia–ischemia. Advances in the understanding of
ongoing injury have facilitated the introduction of targeted
neuroprotective strategies that may improve long-term outcome. Brain injury secondary to intracranial hemorrhage
and/or focal cerebral infarction continues to be identified
only at the time of symptoms greatly limiting attempts at
prevention. Future studies need to focus on identifying highrisk infants that incorporate antepartum, intrapartum and
postpartum strategies.
References
1. Volpe JJ: Hypoxic–ischemic encephalopathy, in Volpe JJ (ed): Neurology of the Newborn. Philadelphia, PA, WB Saunders Company, 2001
2. Perlman JM: Intrapartum hypoxic-ischemic cerebral injury and subsequent cerebral palsy: Medico-legal issues. Pediatrics 99:851-859, 1997
3. Hannigan WC, Magbool BA, Cusack TJ, et al: Diagnosis of subdural
hemorrhage in utero. Case Report J Neurosurg 63:977-979, 1985
4. Gunn TR, Mok PM, Becroft DMO: Subdural hemorrhage in utero.
Pediatrics 76:605-610, 1985
5. Towbin A: Central nervous system damage in the human fetus and
newborn infant. Mechanical and hypoxic injury incurred in the fetal–
neonatal period. Am J Dis Child 199:529-542, 1970
6. Hayashi T, Hashimoto T, Fukuda S, et al: Neonatal subdural hematoma
secondary to birth injury: Clinical analysis of 48 survivors. Child Nerv
Syst 3:23-29, 1987
7. Chamnanvanakij S, Rollins N, Perlman JM: Subdural hematoma in
term infants. Pediatr Neurol 26:301-304, 2002
8. Steinbok P, Haw CS, Cochrane DD, et al: Acute subdural hematoma
associated with cerebral infarction in the full term neonate. Pediatr
Neurosurg 23:206-215, 1995
9. Perlman JM: Neonatal cerebrovascular disorders, in Roach ES, Riela AR
(eds): Pediatric Cerbrovascular Disorders. Armonk, NY, Futura Publishing Company, 1995, pp 267-290
10. Trounce JQ, Dodd KL, Fawer CL, et al: Primary thalamic hemorrhage in
the newborn. A new clinical entity. Lancet 1:190-192, 1985
11. Roland EH, Flodmark O, Hill A: Thalamic hemorrhage with intraventricular hemorrhage in the full term neonate. Pediatrics 85:737-742,
1990
12. Lynch JK, Hirtz DG, DeVeber G, et al: Report of the National Institute
of Neurological Disorders and Stroke workshop on perinatal and childhood stroke. Pediatrics 109:116-123, 2002
13. Estan J, Hope P: Unilateral neonatal cerebral infarction in full term
infants. Arch Dis Child Fetal Neonatal Ed 76:F88-F96, 1997
14. Perlman JM, Rollins NK, Evans D: Neonatal stroke: Clinical characteristics and cerebral blood flow velocity measurements. Pediatr Neurol
11:81-84, 1994
15. Ment CR, Duncan C, Erenkrantz RA: Perinatal cerebral infarction. Ann
Neurol 16:559-568, 1984
16. Barmada MA, Mousby J, Shuman RM: Cerebral infarcts with arterial
occlusion in neonates. Ann Neurol 6:495-502, 1979
17. Kraus FT, Acheen VI: Fetal thrombotic vasculopathy in the placenta:
Cerebral thrombi and infarcts, coagulopathies, and cerebral palsy.
Hum Pathol 30:759-769, 1999
18. Thorarensen O, Ryan S, Hunter J, et al: Factor V Leiden mutation: An
Brain injury in the term infant
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
unrecognized cause of hemiplegic cerebral palsy, neonatal stroke, and
placental thrombosis Ann Neurol 42:372-375, 1997
Mercuri E, Cowan F, Gupte G, et al: Prothrombotic disorders and
abnormal neurodevelopmental outcome in infants with neonatal cerebral infarction. Pediatrics 107:1400-1414, 2001
Trauner DA, Mannino FL: Neurodevelopmental outcome after neonatal cerebrovascular accidents. J Pediatr 108:458-461, 1986
Vannucci RC, Perlman JM: Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics 100:1004-1014, 1997
Wyatt JS, Edwards AD, Azzopardi D, et al: Magnetic resonance and
near infrared spectroscopy for investigation of perinatal hypoxic-ischemic brain injury. Arch Dis Child 64:953-963, 1989
Grow J, Barks DE: Pathogenesis of hypoxic-ischemic cerebral injury in
the term infant: Current concepts. Clin Perinatol 29:585-602, 2002
Lorek A, Takei Y, Cady EB, et al: Delayed (“secondary”) cerebral energy
failure after acute hypoxia- ischemia in the newborn piglet: Continuous
48-hour studies by phosphorus magnetic resonance spectroscopy. Pediatr Res 36:699-706, 1994
Roth SC, Baudin J, Cady E, et al: Relation of deranged neonatal cerebral
oxidative metabolism with neurodevelopmental outcome and head circumference at four years. Dev Med Child Neurol 39:718-725, 1997
Palmer C: Hypoxic-ischemic encephalopathy. Therapeutic approaches
against microvascular injury, and role of neutrophils, PAF, and free
radicals. Clin Perinatol 22:481-517, 1995
Hagberg H, Gilliaud E, Bona E: Enhanced expression of IL1 and IL6
m-RNA and bioactive proteins after hypoxia ischemia in neonatal rats.
Pediatr Res 40:603-609, 1996
Bona E, Anderson AL: Chemokines and inflammatory cell response to
hypoxia ischemia in immature rats. Pediatr Res 45:500-509, 1999
Eklind S, Mallard C, Leverin AL: Bacterial endotoxin sensitizes the
immature brain to hypoxic ischemic injury. Eur J Neurosci 13:11011106, 2001
Hagan P, Barks GDE, Yabut M, et al: Adenovirus mediated over expression of IL1 receptor antagonist reduces susceptibility to excitotoxic
brain injury in perinatal rats. Neuroscience 75:1033-1045, 1996
Yanasaki Y, Shoozurhara H, Onodera H, et al: Blocking of IL-1 activity
is a beneficial approach to ischemia and brain edema formation. Acta
Neurochir 60:S300-S302, 1995
Bruce AJ, Boling W, Kindy S: Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF
receptors. Nat Med 2:788-794, 1996
Loddick SA, Turnbill AV, Rothwell NJ: Cerebral interleukin 1 is neuroprotective against permanent focal ischemia in the rat. J Cereb Blood
Flow Metab 18:176-179, 1998
Bonfold E, Krainc D, Ankarcrona M, et al: Apoptosis and necrosis: Two
distinct events, induced respectively by mild and intense insults with N
methyl-dospartate or nitric oxide/superoxide in cortical cell cultures.
Proc Natl Acad Sci U S A 92:7162-7166, 1995
Edwards AD, Mehmet H: Apoptosis in perinatal hypoxic-ischemic cerebral damage. Neuropathol Appl Neurobiol 22:494-498, 1996
Sarnat HB, Sarnat MS: Neonatal encephalopathy following fetal distress. Arch Neurol 33:696-705, 1976
Huppi PS: Advances in postnatal neuroimaging: Relevance to pathogenesis and treatment of brain injury. Clin Perinatol 29:827-856, 2002
Ment LR, Bada HS, Barnes P, et al: Practice parameter: Neuroimaging of
the neonate: Report of the Quality Standards Subcommittee of the
American Academy of Neurology and the Practice Committee of the
Child Neurology Society. Neurology 58:1726-1738, 2002
Cowan FM, Pennock JM, Hanrahan JD, et al: Early detection of cerebral
infarction and hypoxic ischemic encephalopathy in neonates using
diffusion-weighted magnetic resonance imaging. Neuropediatrics 25:
172-175, 1994
Albers GW, Lansberg MG, Norbash AM, et al: Yield of diffusionweighted MRI for detection of potentially relevant findings in stroke
patients. Neurology 54:1562-1567, 2000
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 34:148-151, 1994
423
42. Hanrahan JD, Cox IJ, Edwards AD, et al: Persistent increases in cerebral
lactate concentration after birth asphyxia. Pediatr Res 44:308-311,
1998
43. Perlman JM, Risser R: Can asphyxiated infants at risk for neonatal
seizures be rapidly identified by current high-risk markers? Pediatrics
97:456-462, 1996
44. Hellstrom-Westas L, Rosen I, Svenningsen NW: Predictive value of
early continuous amplitude integrated EEG recordings on outcome
after severe birth asphyxia in full term infants. Arch Dis Child 72:F34F38, 1995
45. al Naqeeb N, Edwards AD, Cowan FM, et al: Assessment of neonatal
encephalopathy by amplitude-integrated electroencephalography. Pediatrics 103:1263-1269, 1999
46. Shalak L, Corbett R, Laptook AR, et al: Amplitude-integrated electroencephalography coupled with an early neurologic examination enhances prediction of term infants at risk for persistent encephalopathy.
Pediatrics 111:351-357, 2003
47. Dzhala V, Ben-Ari Y, Khazipov R: Seizures accelerate anoxia-induced
neuronal death in the neonatal rat hippocampus. Ann Neurol 48:632640, 2000
48. Holmes GL, Gairsa JL, Chevassus-Au-Louis N, Ben-Ari Y: Consequences of neonatal seizures in the rat: Morphological and behavioral
effects. Ann Neurol 44:845-857, 1998
49. Mizrahi EM: Consensus and controversy in the clinical management of
neonatal seizures. Clin Perinatol 16:485-500, 1989
50. Scher MS, Aso K, Beggerly ME, et al: Electrographic seizures in preterm
and full term infant’s neonates: Clinical correlates associated brain lesions and risk for neurologic sequelae. Pediatrics 91:128-134, 1993
51. Goldberg RN, Moscoso P, Bauer CR, et al: Use of barbiturate therapy in
severe perinatal asphyxia: A randomized controlled trial. J Pediatr 109:
851-856, 1986
52. 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 132:345-348, 1998
53. Minamisawa H, Smith ML, Siesjo BK: The effects of mild hyperthermia
and hypothermia on brain damage following 5, 10, and 15 minutes of
forebrain ischemia. Ann Neurol 28:26-33, 1990
54. Yager J, Towfighi, Vannucci RC: Influence of mild hypothermia on
hypoxic-ischemic brain damage in the immature rat. Pediatr Res 35:
525-529, 1993
55. Laptook AR, Corbett RJT, Sterett R, et al: Modest hypothermia provides
partial neuroprotection for ischemic neonatal brain. Pediatr Res 35:
436-442, 1994
56. Thorensen M, Bagenholm R, Loberg EM, et al: Posthypoxic cooling of
neonatal rats provides protection against brain injury. Arch Dis Child
74:F3-F9, 1996
57. Gunn AJ, Gunn TR, de Haan HH, et al: Dramatic neuronal rescue with
prolonged selective head cooling after ischemia in fetal lambs. J Clin
Invest 99:248-256, 1997
58. Gunn AJ, Gunn TR, Gunning MI: Neuroprotection with prolonged
head cooling started before postischemic seizures in fetal sheep. Pediatrics 102:1098-1106, 1998
59. Gunn AJ, Bennet L, Gunning MI, et al: Cerebral hypothermia is not
neuroprotective when started after post ischemic seizures in fetal sheep.
Pediatr Res 46:274-280, 1999
60. Gunn AJ: Cerebral hypothermia for prevention of brain injury following perinatal asphyxia. Curr Opin Pediatr 12:111-115, 2000
61. Colbourne F, Sutherland G, Corbett D: Postischemic hypothermia: A
critical appraisal with implications for clinical treatment. Mol Neurobiol 14:171-201, 1997
62. Edwards AD, Wyatt JS, Thoresen M: Treatment of hypoxic-ischemic
brain damage by moderate hypothermia. Arch Dis Child Fetal Neonatal
Ed 78:F85-F91, 1998
63. Laptook AR, Corbett RJT: Therapeutic hypothermia: A potential neuroprotective and resuscitative strategy for neonatal hypoxia-ischemia.
Prenat Neonat Med 1:199-212, 1996
64. Towfighi J, Housman C, Heitjan DF, et al: The effect of focal cerebral
cooling on perinatal hypoxic-ischemic brain damage. Acta Neuropathol 87:598-604, 1994
424
65. Laptook AR, Corbett RJT: The effects of temperature on hypoxic-ischemic brain injury. Clin Perinat. 29:623-629, 2002
66. Marion DW, Penrod LE, Kelsey SF, et al: Treatment of traumatic brain
injury with moderate hypothermia. N Engl J Med 336:540-546, 1997
67. Bernard SA, Gray TW, Buist MD, et al: Treatment of comatose survivors
of out-of-hospital cardiac arrest with induced hypothermia. N Engl
J Med 346:557-563, 2002
68. Hypothermia after cardiac arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl
J Med 346:549-556, 2002
69. Laptook AR, Shalak L, Corbett RJT: Differences in brain temperature
and cerebral blood flow during selective head versus whole-body cooling Pediatrics 108:1103-1110, 2001
70. Thoresen M, Whitelaw A: Cardiovascular changes during mild therapeutic hypothermia and rewarming in infants with hypoxic-ischemic
encephalopathy. Pediatrics 106:92-99, 2000
71. Gunn AJ, Gluckman PD, Gunn TR: Selective head cooling in newborn
infants after perinatal asphyxia. A safety study. Pediatrics 102:885-892,
1998
72. Azzopardi D, Robertson NJ, Cowan FM, et al: Pilot study of treatment
with whole body hypothermia for neonatal encephalopathy. Pediatrics
106:684-694, 2000
73. Shimizu K, Rajapakse N, Horiguchi T, et al: Neuroprotection against
hypoxia-ischemia in neonatal rat brain by novel superoxide dismutase
mimetics. Neurosci Lett 346:41-44, 2003
74. Van Bel F, Shadid M, Moison RM, et al: Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics and electrical
brain activity. Pediatrics 101:185-193, 1998
75. Peeters-Scholte C, Braun K, Koster J, et al: Effects of allopurinol and
desferoxamine on reperfusion injury of the brain in newborn piglets
after neonatal hypoxia-ischemia. Pediatr Res 54:516-522, 2003
76. Marret S, Gressens P, Gadisseux JF, et al: Prevention by magnesium of
excitotoxic neuronal death in the developing brain: An animal model of
clinical intervention studies. Dev Med Child Neurol 37:473-484, 1995
77. Penrice J, Amess PN, Punwani S, et al: Magnesium sulfate after transient
hypoxia-ischemia fails to prevent delayed cerebral energy failure in the
newborn piglet. Pediatr Res 41:443-447, 1997
J.M. Perlman
78. de Haan HH, Gunn AJ, Williams CE, et al: Magnesium sulfate therapy
during asphyxia in near-term fetal lambs does not compromise the
fetus but does not reduce cerebral injury. Am J Obstet Gynecol 176:
18-27, 1997
79. Nelson KB, Grether JK: Can magnesium sulfate reduce the risk of
cerebral palsy in very low birth weight infants? Pediatrics 95:263-269,
1995
80. Ischiba H: Randomized controlled trial of magnesium sulfate infusion
for severe birth asphyxia Pediatr Int 44:505-509, 2002
81. Levene MI, Gibson NA, Fenton AC, et al: The use of a calcium-channel
blocker, nicardipine, for severely asphyxiated newborn infants. Dev
Med Child Neurol 32:567-574, 1990
82. Liu XH, Eun BL, Silverstein FS, et al: The platelet-activating factor
antagonist BN 52021 attenuates hypoxic-ischemic brain injury in the
immature rat. Pediatr Res 40:797-803, 1996
83. Halle JN, Kasper CE, Gidday JM, et al: Enhancing adenosine A1 receptor binding reduces hypoxic-ischemic brain injury in newborn rats.
Brain Res 759:309-312, 1997
84. Tan WK, Williams CE, Mallard CE, et al: Monosialoganglioside GM1
treatment after a hypoxic-ischemic episode reduces the vulnerability of
the fetal sheep brain to subsequent injuries. Am J Obstet Gynecol
170:663-669, 1994
85. Holtzman DM, Sheldon RA, Jaffe W, et al: Nerve growth factor protects
the neonatal brain against hypoxic-ischemic injury. Ann Neurol 39:
114-122, 1996
86. Johnston BM, Mallard EC, Williams CE, et al: Insulin-like growth factor-1 is a potent neuronal rescue agent after hypoxic-ischemic injury in
fetal lambs. J Clin Invest 97:300-308, 1996
87. Arvin K, Han BH, Du Y, et al: Minocycline markedly protects the
neonatal brain against hypoxic-ischemic injury. Ann Neurol 52:54-61,
2002
88. Aydin A, Genc K, Akhisaroglu M, et al: Erythropoietin exerts neuroprotective effect in neonatal rat model of hypoxic-ischemic brain injury
Brain Dev 25:494-498, 2003
89. Kumral A, Ozer E, Yilmaz O, et al: Neuroprotective effect of erythropoietin o/ hypoxic-ischemic brain injury in neonatal rats. Biol Neonate
83:224-228, 2003