SPECIAL ARTICLE
Interventions for Perinatal Hypoxic–Ischemic Encephalopathy
Robert C. Vannucci, MD*; and Jeffrey M. Perlman, MD, ChB‡
P
erinatal cerebral hypoxia–ischemia remains a
frequent cause of the chronic handicapping
conditions of cerebral palsy, mental retarda-
tion, learning disability, and epilepsy.1 Estimates
suggest that between 2 and 4/1000 full-term new-
born infants suffer asphyxia at or shortly before
birth. Approximately 15% to 20% of such asphyxi-
ated infants who exhibit hypoxic–ischemic encepha-
lopathy actually die during the newborn period, and
of the survivors, 25% will exhibit permanent neuro-
psychologic deficits. Given these incidence figures,
physicians have searched for strategies to prevent or
minimize the long-term consequences of perinatal
cerebral hypoxia–ischemia.
In the past, therapeutic interventions for hypoxic–
ischemic encephalopathy in full-term newborn
infants consisted of those drugs that reduced the
severity of cerebral edema arising from hypoxia–
ischemia.2 Such agents included osmotic diuretics
(mannitol, furosemide), glucocorticosteroids, and
barbiturates. One by one, these drugs and other ma-
nipulations to treat brain swelling have been dis-
carded, such that presently no agent has been proven
useful to ameliorate perinatal hypoxic–ischemic
brain damage in the clinical setting (but see below).
Accordingly, there is no uniform standard of care in
the brain-oriented therapy of full-term newborn in-
fants sustaining cerebral hypoxia–ischemia, and it
remains for future research to uncover new and ef-
fective strategies for the neurologically compromised
infant.
CHARACTERISTICS OF HYPOXIC–ISCHEMIC
BRAIN DAMAGE
Hypoxic–ischemic brain damage is an evolving
process, which begins during the insult and extends
into the recovery period after resuscitation (reperfu-
sion interval).3 Tissue injury takes the form of either
selective neuronal necrosis or infarction, the latter
with destruction of all cellular elements including
neurons, glia, and blood vessels. When infarction
occurs, the immediate area surrounding the infarct
(penumbra) consists of neurons undergoing either
From the *Department of Pediatrics, Pennsylvania State University College
of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania; and
the ‡Department of Pediatrics, University of Texas Southwestern Medical
Center, Dallas, Texas.
Received for publication Jun 8, 1997; accepted Aug 5, 1997.
Reprint requests to (R.C.V.) Department of Pediatrics, Milton S. Hershey
Medical Center, Box 850, Hershey, PA 17033-0850.
PEDIATRICS (ISSN 0031 4005). Copyright © 1997 by the American Acad-
emy of Pediatrics.
1004 PEDIATRICS Vol. 100 No. 6 December 1997
Downloaded from pediatrics.aappublications.org at State Univ Of Ny at Buffalo on January 23, 2015
necrosis or apoptosis (programmed cell death).4 –7 It
is the penumbral area that appears most amenable to
reversal of cellular injury through therapeutic inter-
vention.
At the cellular level, cerebral hypoxia–ischemia
sets in motion a cascade of biochemical events
commencing with a shift from oxidative to anaero-
bic metabolism (glycolysis), which leads to an
accumulation of nicotinamide-adenine-dinucleotide
(NADH), flavin-adenine-dinucleotide (FADH), and
lactic acid plus H1 ions. Anaerobic glycolysis cannot
keep pace with cellular energy demands, resulting in
a depletion of high-energy phosphate reserves, in-
cluding ATP. Transcellular ion pumping fails, lead-
ing to an accumulation of intracellular Na1, Ca11,
Cl2, and water (cytotoxic edema). Hypoxia–ischemia
also stimulates release of excitatory amino acids (glu-
tamate) from axon terminals. The glutamate release,
in turn, activates glutamate cell surface receptors,
resulting in an influx of Na1 and Ca11 ions. Within
the cytosol, free fatty acids accumulate from in-
creased membrane phospholipid turnover and,
thereafter, undergo peroxidation by oxygen-free rad-
icals that arise from reductive processes within mi-
tochondria and as by-products in the synthesis of
prostaglandins, xanthine, and uric acid. Ca11 ions
accumulate within the cytosol as a consequence of
increased plasma (cellular) membrane influx via
voltage-sensitive and agonist-operated calcium
channels and of decreased efflux across the plasma
membrane combined with release from mitochon-
dria and the endoplasmic reticulum. Nitric oxide, a
free-radical gas, is generated via Ca11 activation in
selected neurons and diffuses to adjacent cells that
are susceptible to nitric oxide toxicity. The combined
effects of cellular energy failure, acidosis, glutamate
and nitric oxide neurotoxicity, free radical formation,
Ca11 accumulation, and lipid peroxidation serve to
disrupt structural components of the cell with its
ultimate death (for review, Reference 3).
The therapeutic window is that interval after re-
suscitation from hypoxia–ischemia, during which an
intervention might be efficacious in reducing the
severity of the ultimate brain damage. Because of the
slow process of neuronal necrosis and apoptosis in
adult experimental animals and humans, the thera-
peutic window in adults can extend for several hours
to a day or more.4,8 –10 Such is not the case in perinatal
animals and presumably in human infants, in whom
the process of cellular destruction is much more
rapid than in adults.3 Accordingly, in the full-term
infant, the therapeutic window would be short and
possibly no longer than 1 to 2 hours. In this regard,
no drug has been found efficacious in reducing the
severity of hypoxic–ischemic brain damage in imma-
ture animals when given later than 2 hours after
termination of the hypoxic–ischemic insult (see below).
An additional issue that constantly arises regard-
ing therapeutic intervention of the asphyxiated full-
term newborn infant is the identification of those
infants at highest risk for permanent brain damage.
Given the presumed short therapeutic window, such
infants must be identified as soon after birth as pos-
sible so that an appropriate drug is administered on
arrival in the neonatal intensive care unit. Clinical
investigations suggest that infants at highest risk for
hypoxic–ischemic brain damage include those who
have exhibited progressive fetal heart rate abnormal-
ities shortly before birth, are severely depressed at
birth (very low Apgar scores), exhibit an acidosis
with a pH , 7.0 on umbilical cord blood oxygen and
acid-base analysis, and require major resuscitation in
the delivery room, including cardiac massage and
intubation.11–14 An additional dilemma relates to the
probability that those infants likely to sustain the
greatest hypoxic–ischemic brain damage will benefit
least by any specific therapeutic intervention,
whereas those infants sustaining only mild or mod-
erate brain damage would benefit most by drug ther-
apy. These issues dictate the need for well-con-
trolled, randomized experimental trials of specific
drugs to determine adequately their efficacy in the
clinical setting. Only through such trials will physi-
cians avoid the pitfalls of routinely treating newborn
infants with inappropriate drugs, as has occurred
occasionally.
PHARMACOLOGIC AGENTS UNDER
EXPERIMENTAL INVESTIGATION
Given the absence of an effective management pro-
gram for perinatal hypoxic–ischemic encephalopa-
thy, it is important that physicians and scientists seek
new approaches to the treatment of fetuses and new-
born infants suffering cerebral hypoxia–ischemia.
Drugs currently under intense investigation, espe-
cially in experimental animals, include inhibitors of
oxygen-free radical generation and free-radical scav-
engers, antagonists of excitatory amino acids, cal-
cium channel blockers, and nitric oxide synthase in-
hibitors, among others.
Oxygen-free Radical Inhibitors and Scavengers
A free radical is an atom or a molecule that con-
tains an uneven number of electrons in its outer most
orbital. A free radical, such as zO22 or zOH2, can
combine sequentially with nonradicals, the result of
which are new free radicals. This characteristic en-
ables free radicals to initiate and perpetuate chain
reactions, the peroxidation of unsaturated fatty acids
being a prominent example. In this regard, it is as-
sumed that the manner in which oxygen-free radicals
cause or contribute to brain damage relates to their
ability to attack the fatty acid moiety of plasma and
subcellular membranes.15–17 Polyunsaturated fatty ac-
Downloaded from pediatrics.aappublications.org at State Univ Of Ny at Buffalo on January 23, 2015
ids seem especially prone to peroxidative attack by
free radicals, which initiate and perpetuate chain
reactions within the hydrophobic core of the lipid
bilayer, leading ultimately to membrane fragmenta-
tion. The brain is especially rich in polyunsaturated
phospholipids and, accordingly, is susceptible to free
radical attack. Free iron (Fe; iron not bound to pro-
tein) and nitric oxide (see below) are important con-
tributors to oxidative injury, because they transform
mildly reactive oxygen species to more toxic free
radicals.17,18 Prevention of the formation of these re-
active products can be achieved by elimination of
hydrogen peroxide or superoxide, or the catalyst of
the reaction, specifically Fe.
Because all biological systems generate oxygen-
free radicals even under physiologic conditions, en-
zymes are present within the cell to protect its con-
stituents from the oxidizing effect of hydrogen
peroxide and its metabolic products; these enzymes
include superoxide dismutase, endoperoxidase, and
catalase, which convert hydrogen peroxide to either
water or stable oxygen. Additional defenses are pro-
vided by endogenous scavengers, which include
cholesterol, a-tocopherol (vitamin E), ascorbic acid
(vitamin C), and thiol-containing compounds, nota-
ble glutathione. Thus, cells including neurons are
capable of rapidly destroying free radicals, once
formed, via both enzymatic and nonenzymatic
quenching.
Oxygen-free radicals are generated during and af-
ter hypoxia–ischemia in several ways. First, free rad-
icals are produced within mitochondria when cyto-
chrome oxidase is not fully saturated with oxygen,
thereby liberating free radicals at more proximal
steps. These oxygen-free radicals cannot be con-
sumed further and leak out into the cytoplasm. Other
sources of oxygen-free radicals during hypoxia–isch-
emia and especially during the reperfusion interval
of recovery are as by-products in the synthesis of
prostaglandins from arachidonic acid19 –21 and the
conversion of hypoxanthine to xanthine and uric
acid.16,22,23 Therefore, drugs that inhibit the formation
of oxygen-free radicals or that rapidly destroy free
radicals, once formed, might be efficacious in reduc-
ing the severity of hypoxic–ischemic brain damage.
Free radicals and reactive oxygen species (super-
oxide and hydrogen peroxide) cause tissue injury
only when the radicals exceed the brain’s endoge-
nous antioxidant defenses. The newborn human in-
fant, especially the premature infant, might be par-
ticularly susceptible to free radical injury because of
a relative deficiency in the brain’s antioxidants, in-
cluding the enzymes superoxide dismutase and glu-
tathione peroxidase.24,25 The premature infant also
has low circulating levels of glutathione and a rela-
tive inability to sequester Fe because of low trans-
ferrin levels.26
One therapeutic approach to the early destruction
of oxygen-free radicals generated during and after
hypoxia–ischemia has been the administration of
specific enzymes known to degrade highly reactive
radicals to nonreactive compounds. The administra-
tion of the antioxidant enzymes superoxide dis-
mutase and catalase conjugated to polyethylene
SPECIAL ARTICLE 1005
glycol has been shown to reduce hypoxic–ischemic
brain damage and to maintain the stability of the
blood– brain barrier.27–29 The enzymes are conjugated
to polyethylene glycol to prolong their half-life and
to allow improved penetration into and across the
endothelial cell layer of the blood– brain barrier. Un-
fortunately, these large molecules are restricted pri-
marily to the vascular compartment, where they con-
tribute to the destruction of reactive oxygen species
generated within blood during reperfusion after hy-
poxia–ischemia. The prolonged interval required for
the conjugated enzymes to penetrate the blood– brain
barrier into brain parenchyma precludes their clini-
cal usefulness in reperfusion injury. In this regard,
the enzymes have a narrow therapeutic dosage range
and are generally protective only when administered
many hours before the hypoxic–ischemic insult.
Drugs potentially efficacious in favorably influenc-
ing the outcome of hypoxic–ischemic brain damage
include agents that inhibit specific reactions in the
production of prostaglandins and of xanthine, the
formation of which involves the generation of oxy-
gen-free radicals (see above). Both allopurinol and
oxypurinol, which are xanthine oxidase inhibitors/
scavengers, protect immature rats from hypoxic–
ischemic brain damage even when the drugs are
administered early during the recovery phase after
resuscitation.30 –32 Indomethacin, a cyclooxygenase
and phospholipase inhibitor, also has been shown to
ameliorate ischemic brain damage, at least in adult
animals,33 and substantially reduces free radical gen-
eration during reperfusion from hypoxia–ischemia in
newborn pigs.34 Finally, members of a class of com-
pounds called 21 amino-steroids (lazeroids) have
been shown to be neuroprotective in both adult and
immature animal models of cerebral hypoxia–isch-
emia.35,36 The compounds apparently prevent Fe-de-
pendent lipid peroxidation by scavenging peroxyl
radicals, and their site of action is predominantly
within cerebral blood vessels, thereby reducing
reperfusion injury.
Recent evidence also suggests that circulating and
endogenous inflammatory cells act as mediators of
hypoxic–ischemic injury in the immature brain, pre-
sumably through the production of oxygen-free rad-
icals.37–39 Platelet-activating factor, a potent phospho-
lipid inflammatory mediator, is synthesized in the
brain, and its concentration is increased during cere-
bral ischemia.40 Furthermore, Liu et al40 have shown
in immature rats that the platelet-activating factor
antagonist BN 52021 attenuates hypoxic–ischemic
brain damage. The agent was efficacious even when
given immediately after reperfusion and again at 2
hours after hypoxia–ischemia.
Excitatory Amino Acid Antagonists
Several lines of research in experimental animals
have implicated a role for the excitatory amino acid
glutamate in the production of hypoxic–ischemic
brain damage in the immature and adult brain. First,
glutamate is directly toxic to mature neurons in cul-
ture.41 Second, neurons in culture and hippocampal
slices die on exposure to anoxia, but their death can
be prevented by the presence of magnesium (Mg11),
1006 PERINATAL HYPOXIC–ISCHEMIC ENCEPHALOPATHY
Downloaded from pediatrics.aappublications.org at State Univ Of Ny at Buffalo on January 23, 2015
which blocks glutamate receptors within the calcium
(Ca11) ion channel, or by specific glutamate antago-
nists.42– 44 Third, direct injection of glutamate or glu-
tamate agonists into specific regions of brain in vivo
produces neuronal injury identical to that seen after
hypoxia–ischemia.45– 47 Fourth, deafferentation of the
glutaminergic excitatory input into the hippocampus
reduces the damage produced by hypoxia–isch-
emia.48 These studies provide convincing evidence
that excessive exposure of neurons to glutamate, as
occurs during hypoxia–ischemia, leads to morpho-
logic alterations characteristic of ischemic neuronal
necrosis.
Given the premise that excessive stimulation of
neuronal surface receptors by glutamate promotes
cellular death, and that glutamate release from the
axon terminal into the synaptic cleft occurs during
hypoxia–ischemia,41,49 –51 it has been rational to search
for pharmacologic agents that would either inhibit
glutamate release or block its postsynaptic action.
Inhibitors of glutamate release from the nerve termi-
nal (eg, baclofen) have not been investigated as po-
tential neuroprotective drugs, whereas antagonists
of glutaminergic cell surface receptors have under-
gone extensive study in experimental animals.52,53 Of
the several available antagonists, those that affect the
NMDA and AMPA/QA receptors or the ion chan-
nels they subserve have received the most attention.
Available compounds include phencyclidine, dextro-
methorphan, ketamine, MK-801, and NBQX, among
others. These compounds have been found effica-
cious in reducing the extent of hypoxic–ischemic
brain damage in adult animals even when adminis-
tered up to 24 hours after the metabolic insult.54
Experimental studies in immature animals have
shown that, as in adult animals, glutamate receptor
antagonists are capable of reducing the severity of
hypoxic–ischemic brain damage. First, systemically
administered MK-801 prevents the tissue necrosis
produced by the direct injection of the glutamate
agonist NMDA into the striatum of 7-day postnatal
rats.55 Second, MK-801 protects against hypoxic–isch-
emic brain damage in immature rats even when the
drug is administered during the course of or up to 1
hour after the metabolic insult.55–59 Pretreatment of
the animals entirely prevents tissue injury.58 The pro-
tective effect of MK-801 or MBQX, which exceeds by
far the effect of other glutamate receptor antagonists,
appears greater in immature rats compared with
their adult counterparts.55,60 The age-related differ-
ence in the efficacies of the glutamate receptor an-
tagonists favoring the immature brain appears to
reside in the sensitivity of the developing brain to
excitatory neurotransmitter toxicity, which in turn
arises from developmental alterations in the density
and distribution of glutamate receptor subtypes,61– 63
in glutamate binding to its receptors, or in trans-
membrane biochemical events initiated by receptor
activity. Indeed, it has been suggested that the
NMDA and AMPA receptor antagonists presently
are the most potent drugs available to ameliorate the
potential devastating effect of cerebral hypoxia–isch-
emia.53
As noted previously, the divalent cation Mg11 acts
as a glutamate receptor antagonist to the extent that
it blocks the neuronal influx of Ca11 within the ion
channel. In this regard, magnesium sulfate has been
shown to reduce the severity of hypoxic–ischemic
brain damage in immature rats.64 – 66 However, the
solution does not improve neuropathologic outcome
when administered before and during the course of
asphyxia produced by umbilical cord occlusion in
near-term fetal lambs.67 In this model, magnesium
caused no greater alterations in systemic blood pres-
sure, heart rate, or cerebral blood flow than that seen
in nontreated fetuses subjected to asphyxia. In the
clinical setting, a retrospective study has suggested
that premature fetuses whose mothers received mag-
nesium sulfate for the treatment of preeclampsia or
as a tocolytic agent are less likely to develop cerebral
palsy compared with a gestational age-matched
group of fetuses not exposed to the drug.68 Based on
the investigation, Nelson and Grether speculated
that magnesium sulfate might provide a protective
effect against brain damage in immature fetuses and
newborn infants. Indeed, Levene et al currently are
conducting a controlled, randomized trial to deter-
mine the protective effect of magnesium sulfate in
asphyxiated full-term infants.69
Calcium Channel Blockers
Because of its multiple functions, calcium (Ca11)
often is considered an intracellular second messen-
ger. The divalent cation is intimately involved as a
cofactor in numerous biochemical reactions, thereby
acting as a regulator of cellular metabolic homeosta-
sis. Accordingly, a disruption of intracellular free
Ca11 concentrations has wide-ranging deleterious
effects on neuronal function.15,49
The mechanisms by which alterations in Ca11 bal-
ance that occur during cerebral hypoxia–ischemia con-
tribute to brain damage relate to disturbances in those
biochemical reactions subserved by the cation.70 Ca11
activates numerous intracellular reactions, the contin-
ued stimulation of which by elevated concentrations of
free Ca11 compromises the viability of the neurons.
These reactions include the activation of several lipases,
proteases, and endonucleases, all of which attack the
structural integrity of the cell. Ca11 also activates phos-
pholipase C, which promotes a progressive breakdown
in the phospholipid components of the plasma and
subcellular membranes. Ca11 also contributes to the
formation of oxygen-free radicals via the formation of
xanthine and prostaglandins (see above). Finally, in-
creased concentrations of intracellular Ca11 lead to an
uncoupling of oxidative phosphorylation within mito-
chondria, because the energy formed during recovery
from hypoxia–ischemia is consumed immediately in an
attempt to reverse and then maintain the electrochem-
ical (ion) gradient across the mitochondrial membrane.
This futile cycling of ions restricts the production and
transfer of ATP into the cytosol to be used for structural
repair and reestablishment of ion gradients across the
plasma membrane. Taken together, the toxic effects of
excessive free Ca11 accumulation are adequate to cause
membrane disintegration and death of the neuron.49,70
Given the potential neurotoxicity of Ca11 when
free intracellular concentrations increase to danger-
Downloaded from pediatrics.aappublications.org at State Univ Of Ny at Buffalo on January 23, 2015
ous levels, drugs have been developed that inhibit
Ca11 influx into neurons. Of the numerous calcium
channel blockers currently available for experimental
and clinical research, flunarizine and nimodipine
appear most efficacious in reducing the extent of
hypoxic–ischemic brain damage, at least in adult
animals.71–73 Furthermore, several investigators inde-
pendently have shown an amelioration of neuro-
pathologic alterations in immature rats subjected to
hypoxia–ischemia and pretreated with the Ca11
channel blocker flunarizine.74 –76 However, the neuro-
protective effect of calcium channel blockers is not
nearly as great as that of the excitatory amino acid
antagonists in the experimental setting, and any ef-
ficacy of the calcium channel blockers in the clinical
setting has been marginal at best.53 Also in the clin-
ical setting, Levene et al77 administered the calcium
channel blocker nicardipine to four severely asphyx-
iated newborn infants. Heart rate increased in all
four infants, whereas mean arterial blood pressure
decreased in three. Two infants had a sudden and
dramatic fall in systemic blood pressure. As a result
of their findings, the investigators cautioned against
the use of these drugs in asphyxiated infants.
Inhibitors of Nitric Oxide Production
Recently, experiments suggest that the free radical
gas nitric oxide (NO) is involved in the cascade of
metabolic events that causes or contributes to the
occurrence of hypoxic–ischemic brain damage.78 – 80
NO is produced in selective neurons of the brain, and
the pathway for its synthesis involves the direct con-
version of l-arginine to citrulline by the catalytic,
cytosolic enzyme NO synthase. NO production is
linked to the activation of glutamate cell surface
receptors, especially NMDA receptors, the activation
of which leads to Ca11 influx into neurons and its
binding to calmodulin (see above). Once formed, NO
influences numerous metabolic events, primarily
through an activation of the second messenger en-
zyme guanylate cyclase with the formation of cyclic
GMP. In excessive concentrations, NO can act as a
neurotoxic agent and might constitute a final com-
mon pathway for amino acid excitotoxicity in the
brain, as has also been proposed for Ca11.15 Experi-
ments in adult animals suggest that NO mediates
neuronal death after cerebral ischemia,81,82 and that
the severity of neuronal loss can be reduced by the
previous administration of inhibitors of NO synthase
activity.83– 85 A similar protective effect also has been
observed in the immature rat subjected to cerebral
hypoxia–ischemia,86,87 but NO synthase inhibition
appears to accentuate neuronal injury in fetal
sheep.88
The mechanisms whereby NO functions as a neu-
rotoxin are numerous. Being a free radical, NO can
react with other free radicals to form even more
reactive species, including the hydroxyl free radi-
cal.18 NO also activates the glycolytic enzyme glyc-
eraldehyde 3-phosphate dehydrogenase.89 Paralysis
of the glycolytic pathway would curtail the cytosolic
production of ATP and prevent the production of
reducing equivalents available to mitochondria for
additional energy production. NO also inhibits com-
SPECIAL ARTICLE 1007
ponents of the mitochondrial electron transport
chain as well as the tricarboxylic acid cycle enzyme
aconitase.90,91 Thus, the neurotoxic effect of NO in
part relates to its capacity to disrupt oxidative me-
tabolism.
Monosialogangliosides
Monosialogangliosides or glycosphingolipids are
found in high concentrations in the brain and are
important constituents of cellular membranes. When
administered systemically, the monosialoganglioside
GM1 crosses the blood– brain barrier and is incorpo-
rated into neuronal cell membranes.92 Recently, it has
been demonstrated that both pre- and posttreatment
with GM1 protects the near-term sheep fetus from
hypoxic–ischemic brain damage.93,94 When given as
an infusion over 6 hours beginning immediately after
reperfusion, the ganglioside improves recovery of
cerebral edema and reduces neuronal injury, espe-
cially in cerebral cortex, hippocampus, and striatum.
The exact mechanism whereby GM1 protects the
brain from hypoxic–ischemic injury is unknown, but
possibly its incorporation into cellular membranes
results in a stabilization of membrane integrity and
function.94
Growth Factors
Many factors are important for normal growth and
maturation of the brain. Accordingly, it is not sur-
prising that such growth factors would be altered by
cerebral hypoxia–ischemia, and that their adminis-
tration might be neuroprotective. Thus far, nerve
growth factor has been shown to reduce the severity
of hypoxic–ischemic brain damage in the immature
rat.95 Other growth factors might be similarly effica-
cious.
Glucocorticosteroids: A Special Case
As briefly mentioned previously, glucocorticoste-
roids have been used previously in human infants,
children, and adults to reduce the cerebral edema
that arises from hypoxia–ischemia. However, con-
trolled clinical studies on the use of either low- or
high-dose steroids, predominantly in adult patients
suffering traumatic coma, indicate that these drugs
fail to attenuate increases in intracranial pressure or
improve ultimate neurologic outcome.96 –98 Experi-
mental studies also suggest that glucocorticosteroid
therapy is ineffective in reducing either the cerebral
edema or the ultimate neuropathologic alterations
that accompany ischemic stroke in adult ani-
mals.99 –101 Relevant to the perinatal brain, Altman et
al102 administered dexamethasone (40 mg/kg) to im-
mature rats immediately before the onset of cerebral
hypoxia–ischemia. The results showed that not only
was the extent of brain damage not different in the
steroid-treated animals compared with nontreated
controls, but also that mortality in the treated rat
pups was greater than that in the control animals
(but see Reference 103). Accordingly, based on both
clinical and experimental data, glucocorticosteroids
administered either shortly before or after cerebral
hypoxia–ischemia does not improve neurologic or
1008 PERINATAL HYPOXIC–ISCHEMIC ENCEPHALOPATHY
Downloaded from pediatrics.aappublications.org at State Univ Of Ny at Buffalo on January 23, 2015
neuropathologic outcome and might increase mor-
bidity and mortality.
Remote or chronic administration of glucocorti-
coids now appears to have a protective benefit. Barks
et al104 found a protective effect of dexamethasone on
hypoxic–ischemic brain damage in the immature rat
when the drug was administered $24 hours before
the metabolic insult. A single low dose (0.1 mg/kg)
given 24 hours before hypoxia–ischemia prevented
cerebral infarction. A single dose given 0 to 3 hours
before hypoxia–ischemia was not effective (see also
Reference 102). In a more recent study, Chumas et
al105 showed that pretreatment of immature rats with
dexamethasone 6 hours before hypoxia–ischemia
also offered protection with no infarction. Additional
studies by the same research group have shown that
the improved neuropathologic outcome afforded to
the dexamethasone-treated immature rats is not the
result of improved cerebral blood flow during hy-
poxia–ischemia.106 Furthermore, the mild hypergly-
cemia observed in the steroid-treated animals does
not account for the cerebral protection, and there also
is no induction of antioxidant enzymes.107
The mechanism(s) by which glucocorticosteroid
therapy protects the developing brain from hypoxic–
ischemic brain damage has yet to be elucidated.
Given the fact that the drug is most efficacious when
given $24 hours before cerebral hypoxia–ischemia in
the immature rat, the interval between the treatment
and the onset of the metabolic stress is adequate to
allow for some form of molecular or cellular adap-
tation that offers protection to occur. A somewhat
analogous situation occurs with hypoxic precondi-
tioning (see below). Additional experiments hope-
fully will elucidate the mechanism whereby glu-
cocorticosteroids provide such a dramatic protective
effect on the immature brain subjected to hypoxia–
ischemia. However, it must be kept in mind that an
interval of 1 day in the developing rat brain is prob-
ably equivalent to 1 month in the human fetus or
newborn infant. On the other hand, glucocorticoste-
roids reduce the incidence and severity of respiratory
distress syndrome when administered to premature
newborn infants within 24 hours of delivery and—
directly or indirectly—reduce the risk of periven-
tricular/intraventricular hemorrhage.108 –111
Phenobarbital: Another Special Case
Numerous investigations have indicated that bar-
biturate pretreatment and even early posttreatment
of adult animals subjected to cerebral hypoxia–isch-
emia reduces the severity of ultimate brain dam-
age.112–115 Experiments also suggest that barbiturates
protect the fetus and newborn animal against as-
phyxia by prolonging survival and by preventing or
reducing the subsequent development of hypoxic–
ischemic brain injury.116 –118 The type of barbiturate
used in all of these experimental studies have been of
the short-acting variety, specifically, thiopental or
pentobarbital. The mechanism(s) of the neuroprotec-
tion relates predominantly to an overall suppression
of cerebral oxidative metabolism, as reflected in a
reduction in oxygen consumption and a slower de-
pletion of energy stores during hypoxia–ischemia or
ischemia.119 –121 Barbiturates might also blunt cerebral
excitotoxicity by depressing glutamate responses
within the brain.122
High-dose barbiturates have been administered to
newborn infants sustaining cerebral hypoxia–isch-
emia before or at the time of delivery.123–125 In a
controlled clinical study, Goldberg et al124 randomly
assigned 32 full-term, severely asphyxiated newborn
infants to barbiturate-treated and control groups. All
newborn infants exhibited evidence of hypoxic–isch-
emic encephalopathy and required mechanical ven-
tilation. Thiopental was begun at a mean postnatal
age of 2 hours and was given as an infusion for 24
hours. Despite barbiturate therapy, no significant
difference in the frequency of seizures or in eleva-
tions in intracranial pressure was noted between the
two groups. Early treatment with thiopental did not
improve neonatal mortality or neurologic morbidity
at 12 months of age. Of additional importance was
the fact that systemic hypotension occurred signifi-
cantly more often in the treated group, requiring
greater vasopressor support in these infants. The
investigators concluded that barbiturate therapy of-
fers little benefit to the previously asphyxiated new-
born infant and might actually perpetuate existing
cardiovascular derangements.
However, a recent clinical investigation by Hall et
al126 has demonstrated a beneficial effect of high-dose
phenobarbital on neurologic outcome in severely as-
phyxiated full-term newborn infants. Twenty as-
phyxiated newborn infants received an intravenous
infusion of phenobarbital (40 mg/kg) between 1 and
6 hours after birth. Twenty infants served as controls.
Thirty-one infants successfully completed the study
(15 treated, 16 controls). Control infants received
phenobarbital (20 mg/kg) only if and when clinically
apparent seizures occurred. No difference in the fre-
quency of seizures was seen in the two groups. In
addition, no adverse effects on heart rate, respiratory
rate, blood pressure, or arterial blood gases were
observed in the high-dose phenobarbital-treated
group. Three-year follow-up revealed normal neuro-
logic outcome in 10 of 15 infants in the treatment
group but in only 3 of 16 infants in the control group
(P , .05). From the findings, the authors concluded
that early high-dose phenobarbital therapy to se-
verely asphyxiated full-term newborn infants ap-
pears to be safe and is associated with significant
improvement in neurologic outcome at 3 years of
age.
The clinical investigation of Hall et al126 is impor-
tant in several respects. First, phenobarbital is a drug
frequently used by neonatologists for the treatment
of seizures in newborn infants. Second, no adverse
systemic physiologic effects were noted. Third, the
drug appeared to be efficacious in ultimately reduc-
ing the severity of hypoxic–ischemic brain damage,
at least from a functional perspective. A controlled,
prospective study with a larger number of asphyxi-
ated newborn infants would be worthwhile.
COMBINATION THERAPY
The issue remains as to whether a combination of
therapeutic agents would be more efficacious in re-
Downloaded from pediatrics.aappublications.org at State Univ Of Ny at Buffalo on January 23, 2015
ducing the severity of hypoxic–ischemic brain dam-
age rather than a single drug. Such might be the case,
given the observation in experimental animals that a
cascade of metabolic events occurs during hypoxia–
ischemia and during recovery after resuscitation that
collectively result in brain damage.70 However, sev-
eral questions arise regarding the use of combination
therapy. First, should the chosen drugs (or other
intervention) be given in parallel or in sequence; if
given in sequence, when? Second, is it possible that
one drug will diminish or even abolish the efficacy of
another drug? Third, will adverse side effects of two
or more drugs more likely occur or become more
prominent than of one drug? Clearly, the use of a
single agent in the clinical setting is the logical first
step, as these questions are answered in the experi-
mental laboratory.
NONPHARMACOLOGIC INTERVENTIONS
In addition to the potentially new pharmaco-
logic strategies to protect the perinatal brain from
hypoxic–ischemic brain damage, several nonphar-
macologic approaches have proved beneficial.
These interventions include hyperglycemia, mild
hypercapnia, systemic or local hypothermia, and
hypoxic preconditioning. These influences on
perinatal hypoxic–ischemic brain damage are ad-
dressed briefly.
Hyperglycemia
Several investigations have indicated that hyper-
glycemia superimposed on cerebral hypoxia–isch-
emia or isolated ischemia accentuates brain damage
in adult experimental animals and humans.127–130
Such is not the case in perinatal animals, at least in
the immature rat. In this regard, Vannucci and Mu-
jsce131 demonstrated that hyperglycemia to blood
glucose concentrations in the range of 600 mg/dL
entirely prevents the occurrence of brain damage in
an immature rat model of cerebral hypoxia–isch-
emia. Hyperglycemia with blood glucose concentra-
tions ranging from 300 to 400 mg/dL has no benefi-
cial effect, nor is it deleterious to the brain subjected
to hypoxia–ischemia.132 Additional investigations
have shown that hyperglycemia superimposed on
cerebral hypoxia–ischemia results in an enhanced
anaerobic glycolytic flux compared with normogly-
cemic controls.133 The enhanced glycolysis, in turn,
leads to better preservation of cerebral high-energy
reserves in the hyperglycemic animals, thus account-
ing for the greater resistance of these animals to
hypoxic–ischemic brain damage. However, hyper-
glycemia has been shown to increase hypoxic–isch-
emic brain damage in newborn pigs,134 in contrast to
the findings in immature rats. In addition, glucose
supplementation during recovery after resuscitation
from cerebral hypoxia–ischemia appears to accentu-
ate brain damage in immature rats.135
In contrast to hyperglycemia, mild insulin-induced
hypoglycemia is detrimental to immature rat brain
subjected to hypoxia–ischemia.136 However, if hypo-
glycemia is induced by fasting the animals for 12
hours, a high degree of protection is afforded to the
brain during hypoxia–ischemia. The fasting is asso-
SPECIAL ARTICLE 1009
ciated with increased concentrations of blood b-hy-
droxybutyrate and acetoacetate concentrations,
which presumably serve as alternate substrates to
the immature brain, thereby protecting it from hy-
poxic–ischemic damage.136 It has been shown that
ketone bodies enter the immature brain more readily
than glucose;137 their ready availability for oxidative
metabolism even under conditions of cerebral hy-
poxia–ischemia provides the necessary reducing
equivalents to preserve high-energy phosphate
reserves during metabolic stress.
Based on the experimental studies described
above, it appears prudent that blood glucose concen-
trations be maintained within a physiologic range
during and after cerebral hypoxia–ischemia in fe-
tuses and newborn human infants. Hypoglycemia
appears to be deleterious, whereas the data regard-
ing any potential beneficial effect of hyperglycemia
during and after hypoxia–ischemia presently are
controversial. Clinical investigations are necessary to
determine whether an infusion of ketone bodies
might protect the perinatal brain from hypoxic–isch-
emic injury.
Carbon Dioxide
Recent clinical investigations suggest that prema-
ture infants who require mechanical ventilation to
prevent or minimize hypoxemia arising from respi-
ratory distress syndrome are at increased risk for the
development of periventricular leukomalacia if hy-
pocapnia occurs during the course of respiratory
management.138 –140 A causal relationship between
low Paco2 and hypoxic–ischemic brain damage was
not established in any of the studies, but given the
multiple effects of carbon dioxide (co2) on hemody-
namics and cerebral metabolism, a cause and effect
relationship is certainly plausible. The question re-
mained as to the contribution of hypocapnia to hy-
poxic–ischemic brain damage and whether hyper-
capnia is neuroprotective.
To resolve the issue, Vannucci et al141 subjected
immature rats to cerebral hypoxia–ischemia with or
without co2 added to the hypoxic gas mixture to
which the animals were exposed. The results showed
that normocapnic (Pco2 5 39 mm Hg) cerebral hy-
poxia–ischemia is associated with less severe brain
damage than hypocapnic (Pco2 5 26 mm Hg) hy-
poxia–ischemia, and that mild hypercapnia (Pco2 5
54 mm Hg) is more protective than normocapnia.
Additional studies were conducted that determined
that mild hypercapnia is associated with greater
preservations of cerebral blood flow, glucose utiliza-
tion, and high-energy phosphate reserves than seen
during either hypocapnic or normocapnic cerebral
hypoxia–ischemia.142 From their findings, the inves-
tigators recommended additional corroboration in
other animal models as well as as a clinical reap-
praisal of the ventilatory management strategies of
sick newborn human infants, as regard especially the
prevention of hypocapnia and the occurrence of per-
missive mild hypercapnia.
It must be emphasized that the apparent neuro-
protective effect of mild hypercapnia seen in imma-
ture rats occurs in the setting of cerebral hypoxia–
1010 PERINATAL HYPOXIC–ISCHEMIC ENCEPHALOPATHY
Downloaded from pediatrics.aappublications.org at State Univ Of Ny at Buffalo on January 23, 2015
ischemia extending over 2.5 hours.141 It is also likely
that the deleterious effect of hypocapnia seen in hu-
man premature infants occurs in the setting of cere-
bral hypoxia–ischemia extending over $1 hours. It
remains to be determined whether hypercapnia is at
least partially protective in the setting of acute intra-
partum asphyxia occurring in full-term human new-
born infants. In this regard, Low et al12 found no
evidence of newborn complications, including en-
cephalopathy, in full-term fetuses in whom only a
respiratory acidosis was apparent on umbilical blood
acid-base analysis. A metabolic acidosis was associ-
ated with a high rate of newborn complications.
Goodwin et al11 showed that full-term newborn in-
fants with respiratory acidemia at birth did not differ
significantly with respect to newborn multiorgan in-
jury compared with infants with similar umbilical
blood pH, but there was a trend toward a lower
incidence of hypoxic–ischemic encephalopathy (P 5
.06). In contrast, van den Berg et al143 found more
newborn complications, including encephalopathy,
in a group of premature and full-term newborn in-
fants born with combined respiratory and metabolic
acidosis than in infants with a metabolic acidosis
alone. Accordingly, it remains to be determined
whether hypercapnia in the setting of acute asphyxia
accentuates or reduces perinatal hypoxic–ischemic
brain damage.
Hypothermia
Systemic or focal cooling of the brain by as little as
3° to 6°C has been shown to reduce the extent of
tissue injury that follows several cerebral insults in
adult experimental animals, including stroke,
trauma, and hypoglycemia.144 –146 In contrast, hyper-
thermia to 38° to 39°C accentuates ischemic brain
damage.147–149 Hypothermia also protects the perina-
tal brain from hypoxic–ischemic damage. In this re-
gard, Yager et al150 demonstrated in immature rats
that a reduction in systemic temperature by 3°C dur-
ing cerebral hypoxia–ischemia provides partial ben-
efit, and a 6°C decrease completely protects the brain
from injury (see also Reference 151). Presumably,
hypothermia reduces cerebral energy demands, such
that during hypoxia–ischemia, high-energy phos-
phate reserves are maintained at relatively normal
levels.152 Systemic hypothermia during the first 3
hours of reperfusion after hypoxia–ischemia also
protects the immature rat brain from damage,153 al-
though this observation has not been universal.150
Similar findings have been observed in newborn
pigs.154,155 Selective cooling of immature rat brain to
temperatures comparable with that of mild systemic
cooling (see above) also affords protection from hy-
poxic–ischemic injury.156 It has been known for de-
cades that systemic cooling of human infants to tem-
peratures ranging from 16° to 24°C protects their
brains from ischemic damage during total circulatory
arrest for up to 90 minutes; this intervention is the
mainstay of the operative correction of congenital
heart defects.157–159
Hypoxic Preconditioning
Recently, it has been demonstrated that immature
rats subjected to cerebral hypoxia–ischemia sustain
less brain damage if they were exposed previously to
systemic hypoxia alone compared with animals not
exposed previously to hypoxia.160 The finding is
comparable with the protective influence of isch-
emic preconditioning on subsequent ischemic
brain damage in adult animals.161–163 The underly-
ing mechanism(s) for the neuroprotection of hy-
poxic preconditioning in the immature animal has
not been elucidated but probably involves the in-
duction of genes or proteins that favorably influ-
ence metabolic events that occur either during the
course of hypoxia–ischemia or in the reperfusion
period after resuscitation. That hypoxic precondi-
tioning protects the immature brain from subse-
quent hypoxic–ischemic brain damage is reminis-
cent of the physiologic hypoxia to which the
human newborn infants is exposed during fetal
life. Whether the physiologic fetal hypoxia is a
preconditioning event, protecting the fetus from
subsequent hypoxic–ischemic brain injury, is con-
jectural. However, Vannucci and Duffy164 have
demonstrated that term fetal rats exposed to a total
nitrogen atmosphere (anoxia) at birth survive
twice as long as newborn rats similarly exposed
despite an age difference of ,24 hours.
CONCLUSIONS
Since the original article on management strategies
for perinatal hypoxic–ischemic encephalopathy that
appeared in Pediatrics in 1990,2 much progress has
been made toward elucidating those pharmacologic
and nonpharmacologic interventions that might pro-
tect the fetus or newborn human infant from hypoxic–
ischemic brain damage. Pilot studies have or are
being conducted currently, and hopefully will pro-
vide at least preliminary information regarding
which interventions will protect the immature brain
from neuronal injury. Additional controlled, pro-
spective trials are warranted, which hopefully will be
designed and conducted within the next few years.
As discussed in the introductory remarks, between
2 and 4/1000 full-term newborn infants suffer as-
phyxia at or shortly before birth. Assuming that 10%
of these infants ultimately suffer permanent brain
damage, the incidence of asphyxia leading to cere-
bral palsy approximates 0.2 to 0.4/1000 infants and
children affected. If there are 4 million full-term
births annually, an incidence of asphyxial brain dam-
age of 0.3/1000 would amount to approximately
1200 afflicted infants born annually. Given the rela-
tively small number of full-term newborn infants
suffering asphyxial brain damage annually, it is not
surprising that neonatal intensive care units through-
out the United States manage only a few such infants
on a yearly basis. It follows that any controlled,
prospective investigation of an intervention strategy
will require a multicenter approach to allow inclu-
sion of an adequate number of infants to achieve any
statistical validity. Such a multicenter trial was the
topic of an open forum held at the 1997 meeting of
Downloaded from pediatrics.aappublications.org at State Univ Of Ny at Buffalo on January 23, 2015
the American Pediatric Society/Society for Pediatric
Research and will be discussed again at Hot Topics
1997.
ACKNOWLEDGMENT
Dr Vannucci’s research is presently supported by National
Institute of Child Health and Human Development Grant P01
HD30704.
REFERENCES
1. Vannucci RC. Hypoxic–ischemic encephalopathy: clinical aspects. In:
Fanaroff AA, Martin RJ, eds. Neonatal–Perinatal Medicine. IV. Philadel-
phia, PA: Mosby-Yearbook, Inc; 1997:877– 891
2. Vannucci RC. Current and potentially new management strategies for
perinatal hypoxic–ischemic encephalopathy. Pediatrics. 1990;85:
961–968
3. Vannucci RC, Palmer C. Hypoxic–ischemic encephalopathy: pathogen-
esis and neuropathology. In: Fanaroff AA, Martin RJ, eds.
Neonatal–Perinatal Medicine. Philadelphia, PA: Mosby-Yearbook, Inc;
1997:856 – 877
4. Memezawa H, Minamisawa H, Smith M-L, et al. Ischemic penumbra in
a model of reversible middle cerebral artery occlusion in the rat. Exp
Brain Res. 1992;89:67–78
5. Linnik MD, Zobrist RH, Hatfield MD. Evidence supporting a role for
program cell death in focal cerebral ischemia in rats. Stroke. 1993;24:
2002–2009
6. Macmanus JP, Buchan AM, Hill IE, et al. Global ischemia can cause
DNA fragmentation indicative of apoptosis in rat brain. Neurosci Lett.
1993;164:89 –92
7. Hossmann K-A. Viability thresholds and the penumbra of focal isch-
emia. Ann Neurol. 1994;36:557–565
8. Horn M, Schlote W. Delayed neuronal death and delayed neuronal
recovery in the human brain following global ischemia. Acta Neuro-
pathol. 1992;85:79 – 87
9. Chiamulera C, Terron A, Reggiani A, et al. Qualitative and quantita-
tive analysis of the progressive cerebral damage after middle cerebral
artery occlusion in mice. Brain Res. 1993;606:251–258
10. Islam N, Aftabuddin M, Moriwaki A, et al. Detection of DNA damage
induced by apoptosis in the rat brain following incomplete ischemia.
Neurosci Lett. 1995;188:159 –162
11. Goodwin TM, Belai I, Hernandez P, et al. Asphyxial complications in
the term newborn with severe umbilical acidemia. Am J Obstet Gynecol.
1992;162:1506 –1512
12. Low JA, Panagiotopoulos C, Derrick EJ. Newborn complications after
intrapartum asphyxia with metabolic acidosis in the term fetus. Am J
Obstet Gynecol. 1994;170:1081–1087
13. Nelson KB, Dambrosia JM, Ting TY, et al. Uncertain value of electronic
fetal monitoring in predicting cerebral palsy. N Engl J Med. 1996;334:
613– 618
14. Perlman JM, Risser R. Can asphyxiated infants at risk for neonatal
seizures be rapidly identified by current high-risk markers? Pediatrics.
1996;97:456 – 462
15. Siesjö BK. Cell damage in the brain: a speculative synthesis. J Cereb
Blood Flow Metab. 1981;1:155–185
16. McCord JM. Oxygen-derived free radicals in postischemic tissue in-
jury. N Engl J Med. 1985;312:159 –163
17. Nelson CW, Wei EP, Povlishock JT, et al. Oxygen radicals in cerebral
ischemia. Am J Physiol. 1992;263:H1356 –H1362
18. Beckman JS, Beckman TW, Chen J, et al. Apparent hydroxyl radical
production by peroxynitrite: implications for endothelial injury from
nitric oxide and superoxide. Proc Natl Acad Sci USA. 1990;87:1620 –1624
19. Majewska M, Strosznajder J, Lazarewicz J. Effect of ischemic anoxia
and barbiturate anesthesia on free radical oxidation of mitochondrial
phospholipids. Brain Res. 1978;158:423– 434
20. Rehncroná S, Westerberg E, Akesson B, et al. Brain cortical fatty acids
and phospholipids during and following complete and severe incom-
plete ischemia. Stroke. 1978;9:327–335
21. Bhakoo KK, Crockard HA, Lascelles PT. Regional studies of changes in
brain fatty acids following experimental ischaemia and reperfusion in
the gerbil. J Neurochem. 1984;43:1025–1031
22. Saugstad OD. Role of xanthine oxidase and its inhibitor in hypoxia:
reoxygenation injury. Pediatrics. 1996;98:103–107
23. de Haan HH, Van Reempts JLH, Vles JSH, et al. Effects of asphyxia on
the fetal lamb brain. Am J Obstet Gynecol. 1993;169:1493–1501
24. Inder TE, Graham P, Sanderson K, et al. Lipid peroxidation as a
measure of oxygen-free radical damage in the very low birthweight
SPECIAL ARTICLE 1011
 infant. Arch Dis Child. 1994;70:107–111
25. Nishida A, Misaki Y, Kuruta H. Developmental expression of copper,
zinc-superoxide dismutase in human brain by chemiluminescence.
Brain Dev. 1994;16:40 – 44
26. Smith CV, Hansen TN, Martin NE, et al. Oxidant stress responses in
premature infants during exposure to hyperoxia. Pediatr Res. 1993;34:
360 –364
27. Liu XH, Kato H, Araki T, et al. An immunohistochemical study of
copper/zinc superoxide dismutase and manganese superoxide dis-
mutase following focal cerebral ischemia in the rat. Brain Res. 1994;
644:257–266
28. Armstead WM, Mirro R, Thelin OP, et al. Polyethylene glycol super-
oxide dismutase and catalase attenuate increased blood– brain barrier
permeability after ischemia in piglets. Stroke. 1992;23:755–762
29. He YY, Hsu CY, Ezrin AM, et al. Polyethylene glycol-conjugated
superoxide dismutase in focal cerebral ischemia reperfusion. Am J
Physiol. 1993;265:H252–H256
30. Palmer C, Vannucci RC, Towfighi J. Reduction of perinatal
hypoxic–ischemic brain damage with allopurinol. Pediatr Res. 1990;27:
332–336
31. Palmer C, Roberts RL. Reduction of perinatal brain damage with
oxypurinol treatment after hypoxic–ischemic injury. Pediatr Res. 1991;
29:362. Abstract
32. Palmer C, Towfighi J, Roberts RL, et al. Allopurinol administered after
inducing hypoxia–ischemia reduces brain injury in 7-day-old rats.
Pediatr Res. 1993;33:405– 411
33. Sasaki T, Nakagomi T, Kirino T, et al. Indomethacin ameliorates isch-
emic neuronal damage in the gerbil hippocampal CA1 sector. Stroke.
1988;19:1399 –1403
34. Pourcyrous N, Leffler CW, Bada HS, et al. Brain superoxide anion
generation in asphyxiated piglets and the effect of indomethacin at
therapeutic dose. Pediatr Res. 1993;34:366 –369
35. Beck T, Bielenberg GW. The effects of 21-aminosteroids on overt
infarct size 48 hours after middle cerebral artery occlusion in the rat.
Brain Res. 1991;560:159 –162
36. Bågenholm R, Andiné P, Hagberg H. Effects of 21-amino steroid
tirilazad mesylate (U74006F) on brain damage and edema after peri-
natal hypoxia–ischemia in the rat. Pediatr Res. 1966;40:399 – 403
37. McRae A, Gilland E, Bona E, et al. Microglia activation after neonatal
hypoxia–ischemia. Dev Brain Res. 1995;84:245–252
38. Towfighi J, Zec N, Yager J, et al. Temporal evolution of neuropatho-
logic changes in an immature rat model of cerebral hypoxia–ischemia:
a light microscopic study. Acta Neuropathol. 1995;90:375–386
39. Ivacko JA, Sun R, Silverstein FS. Hypoxic–ischemic brain injury in-
duces an acute microglial reaction in perinatal rats. Pediatr Res. 1996;
39:39 – 47
40. Liu X-H, Eun B-L, Silverstein FS, et al. The platelet-activating factor
antagonist BN 52021 attenuates hypoxic–ischemic brain injury in the
immature rat. Pediatr Res. 1996;40:1– 8
41. Rothman SM, Olney JW. Glutamate and the pathophysiology of
hypoxic–ischemic brain damage. Ann Neurol. 1986;19:105–111
42. Kass IS, Lipton P. Mechanisms involved in irreversible anoxic damage
to the in vitro rat hippocampal slice. J Physiol (Lond). 1982;332:459 – 472
43. Rothman SM. Synaptic activity mediates death of hypoxic neurons.
Science. 1983;220:536 –527
44. Novelli A, Reilly JA, Lysko PG, et al. Glutamate becomes neurotoxic
via the N-methyl-d-aspartate receptor when intracellular energy levels
are reduced. Brain Res. 1988;451:205–212
45. Coyle JT, Bird SJ, Evans RH, et al. Excitatory amino acid neurotoxins:
selectivity, specificity and mechanism of action. Neurosci Res Prog Bull.
1981;19:329 – 427
46. McBean GJ, Roberts PJ. Chronic infusion of l-glutamate causes neu-
rotoxicity in rat striatum. Brain Res. 1984;290:372–375
47. Steiner HX, McBean GJ, Kohler C, et al. Ibotenate-induced neuronal
degeneration in immature rat brain. Brain Res. 1984;307:117–124
48. Pulsinelli WA. De-afferentation of the hippocampus protects CA1
pyramidal neurons against ischemic damage. Stroke. 1985;16:144. Ab-
stract
49. Siesjö BK, Bengtsson F. Calcium fluxes, calcium antagonists, and cal-
cium-related pathology in brain ischemia, hypoglycemia, and spread-
ing depression: a unifying hypothesis. J Cereb Blood Flow Metab. 1989;
9:127–140
50. Andiné P, Sandberg M, Bågenholm R, et al. Intra- and extracellular
changes of amino acids in the cerebral cortex of the neonatal rat during
hypoxia–ischemia. Dev Brain Res. 1991;64:115–120
51. Silverstein FS, Naik B, Simpson J. Hypoxia–ischemia stimulates hip-
pocampal glutamate efflux in perinatal rat brain: an in vivo microdi-
alysis study. Pediatr Res. 1991;30:587–590
1012 PERINATAL HYPOXIC–ISCHEMIC ENCEPHALOPATHY
Downloaded from pediatrics.aappublications.org at State Univ Of Ny at Buffalo on January 23, 2015
52. Albers G, Goldberg MP, Choi DW. N-methyl-d-aspartate antagonists:
ready for clinical trial in brain ischemia? Ann Neurol. 1989;25:398 – 403
53. McCulloch J. Amelioration of ischemic and hemorrhagic injury by
pharmacological intervention. In: Lou HC, Greisen G, Larsen JF, eds.
Brain Lesions in the Newborn: Hypoxic and Haemodynamic Pathogenesis.
Munksgaard, Copenhagen: 1994;485– 499
54. Sheardown MJ, Suzdak PD, Nordholm L. AMPA, but not NMDA,
receptor antagonism is neuroprotective in gerbil global ischemia, even
when delayed 24 hours. Eur J Pharmacol. 1993;236:347–353
55. McDonald JW, Silverstein FS, Johnston MW. Neuroprotective effects of
MK-801, TCP, PCP, and CPP against N-methyl-d-aspartate induced
neurotoxicity in an in vivo perinatal rat model. Brain Res. 1989;490:
33– 40
56. McDonald JW, Silverstein FS, Johnston MV. MK-801 protects the neo-
natal brain from hypoxic–ischemic damage. Eur J Pharmacol. 1987;140:
359 –361
57. Ford LM, Sanberg PR, Norman AB. Mk-801 prevents hippocampal
neurodegeneration in neonatal hypoxic–ischemic rats. Arch Neurol.
1989;46:1090 –1096
58. Hattori H, Morin AM, Schwartz PH, et al. Posthypoxic treatment with
MK-801 reduces hypoxic–ischemic damage in the neonatal rat. Neurol-
ogy. 1989;39:713–718
59. McDonald JW, Trescher WH, Johnston MV. Susceptibility of brain to
AMPA induced excitotoxicity transiently peaks during early postnatal
development. Brain Res. 1992;583:54 –70
60. Hagberg H, Gilland E, Diemer N-H, et al. Hypoxia–ischemia in the
neonatal rat brain: histopathology after post-treatment with NMDA
and non-NMDA receptor antagonists. Biol Neonate. 1994;66:205–213
61. Greenamyre JT, Olson JMM, Penney JB, et al. Autoradiographic char-
acterization of N-methyl-d-aspartate-, quisqualate- and kainate-
sensitive glutamate binding sites. J Pharmacol Exp Ther. 1985;233:
254 –263
62. Greeyamyre JT, Penney JB, Young AB, et al. Evidence for transient
perinatal glutamatergic innervation of globus pallidus. J Neurosci.
1987;7:1022–1030
63. McDonald JW, Johnston MV. Physiological and pathophysiological
roles of excitatory amino acids during central nervous system devel-
opment. Brain Res Rev. 1990;15:41–70
64. McDonald JW, Silverstein FS, Johnston MV. Magnesium reduces N-
methyl-d-aspartate (NMDA)-mediated brain injury in perinatal rats.
Neurosci Lett. 1990;109:234 –238
65. Thordstein M, Bagenholm R, Thiringer K, et al. Scavengers of free
oxygen radicals in combination with magnesium ameliorate perinatal
hypoxic–ischemic brain damage in the rat. Pediatr Res. 1993;34:23–26
66. Marret S, Gressens P, Gadissiux J-F, et al. Prevention by magnesium of
excitotoxic neuronal death in the developing brain. An animal model
for clinical intervention studies. Dev Med Child Neurol. 1995;37:473– 484
67. de Hann 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. 1997;
176:18 –27
68. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of
cerebral palsy in very low birth weight infants? Pediatrics. 1995;95:
263–269
69. Levene M, Blennow M, Whitelaw A, et al. Acute effects of two differ-
ent doses of magnesium sulphate in infants with birth asphyxia. Arch
Dis Child. 1995;73:F174 –F177
70. Vannucci RC. Experimental biology of cerebral hypoxia–ischemia: re-
lation to perinatal brain damage. Pediatr Res. 1990;27:317–326
71. Deshpande JK, Wieloch T. Flunarizine, a calcium entry blocker, ame-
liorates ischemic brain damage in the rat. Anesthesiology. 1986;64:
215–224
72. Alps BJ, Haas WK. The potential beneficial effect of nicardipine in a rat
model of transient forebrain ischemia. Neurology. 1987;37:809 – 814
73. Germano IM, Bartkowski HM, Cassel ME, et al. The therapeutic value
of nimodipine in experimental focal cerebral ischemia. J Neurosurg.
1987;67:81– 87
74. Silverstein FS, Buchanan K, Hudson C, et al. Flunarizine limits
hypoxia–ischemia induced morphologic injury in immature rat brain.
Stroke. 1986;17:477– 482
75. Gunn AJ, Mydlar T, Bennet L, et al. The neuroprotective actions of a
calcium channel antagonist, flunarizine, in the infant rat. Pediatr Res.
1989;25:573–576
76. Gunn AJ, Williams CE, Mallard EC, et al. Flunarizine, a calcium
channel antagonist, is partially prophylactically neuroprotective in
hypoxic–ischemic encephalopathy in the fetal sheep. Pediatr Res. 1994;
35:657– 663
77. 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. 1990;32:567–574
78. Johns RA. EDRF/nitric oxide. Anesthesiology. 1991;75:927–931
79. Dawson TM, Dawson DL, Snyder SH. A novel neuronal molecular
message in brain: the free radical, nitric oxide. Ann Neurol. 1992;32:
297–311
80. Szabó C. Physiological and pathophysiological roles of nitric oxide in
the central nervous system. Brain Res Bull. 1996;41:131–141
81. Nowicki JP, Duval D, Poignet H, et al. Nitric oxide mediates neuronal
death after focal cerebral ischemia in the mouse. Eur J Pharmacol.
1991;204:339 –340
82. Maiese K, Wagner J, Boccone L. Nitric oxide: a downstream mediator
of calcium toxicity in the ischemic cascade. Neurosci Lett. 1994;166:
43– 47
83. Ashwal S, Cole DJ, Osborne T, et al. Low dose l-NAME reduces infarct
volume in the rat MCAO/reperfusion model. J Neurosurg Anesthesiol.
1993;5:241–249
84. Kuluz JW, Prado RJ, Dietrich WD, et al. The effect of nitric oxide
synthase inhibition on infarct volume after reversible focal cerebral
ischemia in conscious rats. Stroke. 1993;24:2023–2029
85. Nishikawa T, Kirsch JR, Koehler RC, et al. Effect of nitric oxide syn-
thase inhibition on cerebral blood flow and injury volume during focal
ischemia in cats. Stroke. 1993;24:1717–1724
86. Trifiletti RR. Neuroprotective effect of NG-nitro-l-arginine in focal
stroke in the 7-day old rat. Eur J Pharmacol. 1992;218:197–198
87. Hamada Y, Hayakawa T, Hattori H, et al. Inhibitor of nitric oxide
synthesis reduces hypoxic–ischemic brain damage in the neonatal rat.
Pediatr Res. 1994;35:10 –14
88. Marks KA, Mallard CE, Roberts I, et al. Nitric oxide synthase inhibition
attenuates delayed vasodilation and increases injury after cerebral
ischemia in fetal sheep. Pediatr Res. 1996;40:185–191
89. Molina Y, Vedia L, McDonald B, et al. Nitric oxide-induced S-
nitrosylation of glyceraldehyde-3-phosphate dehydrogenase inhibits
enzymatic activity and increases endogenous ADP-ribosylation. J Biol
Chem. 1992;267:24929 –24932
90. Granger DL, Lehninger AL. Sites of inhibition of mitochondrial elec-
tron transport in macrophage-induced neoplastic cells. J Cell Biol.
1982;95:527–535
91. Drapier J-C, Hibbs JC. Murine cytotoxic activated macrophages inhib-
its aconitase in tumor cells. Inhibition involves the iron-sulfur pros-
thetic group and is reversible. J Clin Invest. 1986;78:790 –797
92. Toffano G, Benvegnu D, Bonetti AC. Interaction of GM1 ganglioside
with crude rat brain neuronal membranes. J Neurochem. 1980;35:
861– 866
93. Tan WKM, Williams CE, Gunn AJ, et al. Pretreatment with monosia-
loganglioside GM1 protects the brain of fetal sheep against
hypoxic–ischemic injury without causing systemic compromise. Pedi-
atr Res. 1993;34:18 –22
94. Tan WKM, 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.
1994;170:663– 670
95. Holtzman DM, Sheldon RA, Jaffe W, et al. Nerve growth factor pro-
tects the neonatal brain against hypoxic–ischemic injury. Ann Neurol.
1996;39:114 –122
96. Cooper PR, Moody S, Clark WK, et al. Dexamethasone and severe
head injury: a prospective double-blind study. J Neurosurg. 1979;51:
307–316
97. Gudeman SK, Miller JD, Becker DP. Failure of high-dose steroid ther-
apy to influence intracranial pressure in patients with severe head
injury. J Neurosurg. 1979;51:301–306
98. Dearden NM, Gisbon JS, McDowall DC, et al. Effect of high-dose
dexamethasone on outcome from severe head injury. J Neurosurg.
1986;64:81– 88
99. Plum F, Alvord EC, Posner JB. Effect of steroids on experimental
cerebral infarction. Arch Neurol. 1963;9:571–573
100. Donley RF, Sundt TM. Effect of dexamethasone on the edema of focal
cerebral edema. Stroke. 1973;4:148 –155
101. Lee MC, Mastri RA, Waltz AG, et al. Ineffectiveness of dexamethasone
for treatment of experimental cerebral infarction. Stroke. 1974;5:
216 –218
102. Altman DI, Young RSK, Yagel SK. Effects of dexamethasone in
hypoxic–ischemic brain injury in the neonatal rat. Biol Neonate. 1984;
46:149 –156
103. Kalayci O, Cataltepe S, Cataltepe O. The effect of bolus methylpred-
nisolone in prevention of brain edema in hypoxic–ischemic brain
injury: an experimental study in 7-day-old rat pups. Brain Res. 1992;
569:112–116
Downloaded from pediatrics.aappublications.org at State Univ Of Ny at Buffalo on January 23, 2015
104. Barks JDE, Post M, Tuor UI. Dexamethasone prevents
hypoxic–ischemic brain damage in the neonatal rat. Pediatr Res. 1991;
29:558 –563
105. Chumas PD, Del Bigio MR, Drake JM, et al. A comparison of the
protective effect of dexamethasone to other potential prophylactic
agents in a neonatal rat model of cerebral hypoxia–ischemia. J Neuro-
surg. 1993;79:414 – 420
106. Tuor UI, Simone CS, Barks JDE, et al. Dexamethasone prevents cere-
bral infarction without affecting cerebral blood flow in neonatal rats.
Stroke. 1993;24:452– 457
107. Tuor UI, Simone CS, Arellano R, et al. Glucocorticoid prevention of
neonatal hypoxic–ischemic damage: Role of hyperglycemia and anti-
oxidant enzymes. Brain Res. 1993;604:165–172
108. Garite TJ, Rumney P, Briggs GG, et al. A randomized, placebo-
controlled trial of betamethasone for prevention of respiratory distress
syndrome at 24 – 48 weeks’ gestation. Am J Obstet Gynecol. 1993;166:
646 – 651
109. Leviton A, Kuban KC, Pagano M, et al. Antenatal corticosteroids
appear to reduce the risk of postnatal germinal matrix hemorrhage in
intubated low birthweight babies. Pediatrics. 1993;91:1083–1088
110. Kari M, Hallman M, Eronen M, et al. Prenatal dexamethasone treat-
ment in conjunction with rescue therapy of human surfactant: A
randomized, placebo-controlled, multicenter study. Pediatrics. 1994;93:
730 –736
111. Garland JS, Buck R, Leviton A. Effect of maternal glucocorticoid ex-
posure on risk of severe intraventricular hemorrhage in surfactant-
treated preterm infants. J Pediatr. 1995;126:272–279
112. Michenfelder JD, Milde JH, Sundt TM. Cerebral protection by barbi-
turate anesthesia: use after middle cerebral artery occlusion in Java
monkeys. Arch Neurol. 1976;33:345–350
113. McGraw CP. Experimental cerebral infarction: effects of pentobarbital
in Mongolian gerbils. Arch Neurol. 1977;34:334 –336
114. Bleyaert AL, Nemoto EM, Safar P, et al. Thiopental amelioration of
brain damage after global brain ischemia in monkeys. Anesthesiology.
1978;49:390 –398
115. Levy DE, Brierley JB. Delayed pentobarbital administration limits isch-
emic brain damage in gerbils. Ann Neurol. 1979;5:59 – 64
116. Campbell AGM, Milligan JB, 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
117. 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
118. Goodlin RC, Lloyd D. Use of drugs to protect against fetal asphyxia.
Am J Obstet Gynecol. 1970;107:227–231
119. Wechsler RL, Dripps RD, Kety SS. Blood flow and oxygen consump-
tion of the human brain during anesthesia produced by thiopental.
Anesthesiology. 1951;12:308 –312
120. Lowry OH, Passonneau JV, Hasselberger FX, et al. Effect of ischemia
on known substrates and cofactors of the glycolytic pathway in brain.
J Biol Chem. 1964;239:18 –30
121. Baughman VL, Hoffman WE, Meletich DJ, et al. Effects of phenobar-
bital on cerebral blood flow and metabolism in young and aged rats.
Anesthesiology. 1986;65:500 –505
122. MacDonald RL, Barker JL. Different actions of anticonvulsant and
anesthetic barbiturates revealed by use of cultured mammalian neu-
rons. Science. 1978;200:775–777
123. Eyre JA, Wilkinson AR. Thiopentone induced coma after severe birth
asphyxia. Arch Dis Child. 1986;61:1084 –1089
124. 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
125. Ruth V, Virkola K, Paetau R, et al. Early high-dose phenobarbital
treatment for prevention of hypoxic–ischemic brain damage in very
low birth weight infants. J Pediatr. 1988;112:81– 86
126. Hall RT, Hall FK, Daily DK. High dose phenobarbital therapy in term
newborn infants with severe perinatal asphyxia: a randomized, pro-
spective study with three-year follow-up. J Pediatr. In press
127. Myers RE, Yamaguchi S. Nervous system effects of cardiac arrest in
monkeys. Preservation of vision. Arch Neurol. 1977;34:65–74
128. Kalimo H, Rehncroná S, Suderfeldt B, et al. Brain lactic acidosis and
ischemic cell damage. II. Histopathology. J Cereb Blood Flow Metab.
1981;1:313–327
129. Pulsinelli WA, Waldman S, Rawlinson D, et al. Hyperglycemia con-
verts neuronal damage into brain infarction. Neurology. 1982;32:
1239 –1246
130. Pulsinelli WA, Levy DE, Sigsbee B, et al. Increased damage after
SPECIAL ARTICLE 1013
 ischemic stroke in patients with hyperglycemia with or without dia-
betes mellitus. Am J Med. 1983;74:540 –544
131. Vannucci RC, Mujsce DJ. The effect of glucose on perinatal
hypoxic–ischemic brain damage. Biol Neonate. 1992;62:215–224
132. Voorhies TM, Rawlinson D, Vannucci RC. Glucose and perinatal
hypoxic–ischemic brain damage in the rat. Neurology. 1986;36:
1115–1118
133. Vannucci RC, Brucklacher RM, Vannucci SJ. The effect of hyperglyce-
mia on cerebral metabolism during hypoxia–ischemia in the immature
rat. J Cereb Blood Flow Metab 1996;16:1026 –1033
134. LeBlanc MH, Huang M, Vig V, et al. Glucose affects the severity of
hypoxic–ischemic brain injury in newborn pigs. Stroke. 1993;24:
1055–1062
135. Sheldon RA, Partridge JC, Ferriero DM. Postischemic hyperglycemia is
not protective to the neonatal rat brain. Pediatr Res. 1992;32:489 – 493
136. Yager JY, Heitjan DF, Towfighi J, et al. Effect of insulin-induced and
fasting hypoglycemia on perinatal hypoxic–ischemic brain damage.
Pediatr Res. 1992;31:138 –142
137. Cremer JE. Substrate utilization and brain development. J Cereb Blood
Flow Metab 1982;2:394 – 407
138. Greisen G, Munck H, Lou H. Severe hypocarbia in preterm infants and
neurodevelopmental deficit. Acta Pediatr Scand. 1987;76:401– 404
139. Graziani L, Spitzer AR, Mitchell DG, et al. Mechanical ventilation in
preterm infants: neurosonographic and developmental studies. Pediat-
rics. 1992;90:515–522
140. Ikonen RS, Janas MO, Koidikko MJ, et al. Hyperbilirubinemia, hypo-
carbia and periventricular leukomalacia in preterm infants: Relation-
ship to cerebral palsy. Acta Pediatr Scand. 1992;81:802– 807
141. 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
142. 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
143. van den Berg PP, Nelen WLDM, Jongsma HW, et al. Neonatal com-
plications in newborns with an umbilical artery pH , 7.00. Am J Obstet
Gynecol. 1996;175:1152–1157
144. Busto R, Dietrich WD, Globus MY-T, et al. Small differences in intra-
ischemic brain temperature critically determine the extent of ischemic
neuronal injury. J Cereb Blood Flow Metab. 1987;7:729 –738
145. Clifton GL, Jiang JY, Lyeth BG, et al. Marked protection by moderate
hypothermia after experimental traumatic brain injury. J Cereb Blood
Flow Metab. 1991;11:114 –121
146. Agardh CD, Smith ML, Siesjö BK. The influence of hypothermia on
hypoglycemia-induced brain damage in the rat. Acta Neuropathol. 1992;
83:379 –385
147. Morikawa E, Ginsberg MD, Dietrich WD, et al. The significance of
brain temperature in focal cerebral ischemia: histopathological conse-
quences of middle cerebral artery occlusion in the rat. J Cereb Blood
Flow Metab. 1992;12:380 –389
1014 PERINATAL HYPOXIC–ISCHEMIC ENCEPHALOPATHY
Downloaded from pediatrics.aappublications.org at State Univ Of Ny at Buffalo on January 23, 2015
148. Wass CT, Lanier WL, Hofer RE, et al. Brain changes of #1°C alter
functional neurologic outcome and histopathology in a canine model
of complete cerebral ischemia. Anesthesiology. 1995;83:325–335
149. Kil HY, Zhang J, Piantadosi CA. Brain temperature alters hydroxyl
radical production during cerebral ischemia/reperfusion in rats. J
Cereb Blood Flow Metab. 1996;16:100 –106
150. Yager J, Towfighi J, Vannucci RC. Influence of mild hypothermia on
hypoxic–ischemic brain damage in the immature rat. Pediatr Res. 1993;
34:525–529
151. Young RSK, Olenginski TP, Yagel SK, et al. The effect of graded
hypothermia on hypoxic–ischemic brain damage: a neuropathologic
study in the neonatal rat. Stroke. 1983;14:929 –934
152. Yager JY, Asselin J. Effect of mild hypothermia on cerebral energy
metabolism during the evolution of hypoxic–ischemic brain damage in
the immature rat. Stroke. 1996;27:919 –926
153. Thoresen M, Bågenholm R, Løberg EM, et al. Posthypoxic cooling of
neonatal rats provides protection against brain injury. Arch Dis Child.
1996;74:F3–F9
154. Laptook AR, Corbett RJT, Sterett R, et al. Modest hypothermia pro-
vides partial neuroprotection for ischemic neonatal brain. Pediatr Res.
1994;35:436 – 442
155. Thoresen M, Penrice J, Lorek A, et al. Mild hypothermia after severe
transient hypoxia–ischemia ameliorates delayed cerebral energy fail-
ure in the newborn piglet. Pediatr Res. 1995;37:667– 670
156. Towfighi J, Housman C, Heitjan DF, et al. The effect of focal cerebral
cooling on perinatal hypoxic–ischemic brain damage. Acta Neuropathol.
1994;87:598 – 604
157. Ferry PC. Neurologic sequelae of cardiac surgery in children. Am J Dis
Child. 1987;141:309 –312
158. Greeley WJ, Ungerleider RM, Smith LR, et al. The effects of deep
hypothermic cardiopulmonary bypass and total circulatory arrest on
cerebral blood flow in infants and children. Thorac Cardiovasc Surg.
1989;97:737–745
159. Sealy WC. Hypothermia: its possible role in cardiac surgery. Ann
Thorac Surg. 1989;47:788 –791
160. Gidday JM, Fitzgibbons JC, Shah AR, et al. Neuroprotection from
ischemic brain injury by hypoxic preconditioning in the neonatal rat.
Neurosci Lett. 1994;168:221–224
161. Kato H, Liu Y, Araki T, et al. Temporal profile of the effects of
pretreatment with brief cerebral ischemia on the neuronal damage
following secondary ischemic insult in the gerbil: cumulative damage
and protective effects. Brain Res. 1991;553:238 –242
162. Kirino T, Tsujita Y, Tamura A. Induced tolerance to ischemia in gerbil
hippocampal neurons. J Cereb Blood Flow Metab. 1991;11:299 –307
163. Liu Y, Kato H, Nakata N, et al. Protection of rat hippocampus against
ischemic neuronal damage by pretreatment with sublethal ischemia.
Brain Res. 1992;586:121–124
164. Vannucci RC, Duffy TE. The influence of birth on carbohydrate and
energy metabolism in rat brain. Am J Physiol. 1974;226:933–940
 Interventions for Perinatal Hypoxic−Ischemic Encephalopathy
Robert C. Vannucci and Jeffrey M. Perlman
Pediatrics 1997;100;1004
DOI: 10.1542/peds.100.6.1004
Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/100/6/1004.full.h
tml
References This article cites 160 articles, 37 of which can be accessed
free at:
http://pediatrics.aappublications.org/content/100/6/1004.full.h
tml#ref-list-1
Citations This article has been cited by 31 HighWire-hosted articles:
http://pediatrics.aappublications.org/content/100/6/1004.full.h
tml#related-urls
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Neurology
http://pediatrics.aappublications.org/cgi/collection/neurology_
sub
Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
http://pediatrics.aappublications.org/site/misc/Permissions.xht
ml
Reprints Information about ordering reprints can be found online:
http://pediatrics.aappublications.org/site/misc/reprints.xhtml

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and
trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove
Village, Illinois, 60007. Copyright © 1997 by the American Academy of Pediatrics. All rights
reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at State Univ Of Ny at Buffalo on January 23, 2015

 Interventions for Perinatal Hypoxic−Ischemic Encephalopathy
Robert C. Vannucci and Jeffrey M. Perlman
Pediatrics 1997;100;1004
DOI: 10.1542/peds.100.6.1004

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/100/6/1004.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 1997 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at State Univ Of Ny at Buffalo on January 23, 2015