HIE-Pathophysiology & recent advances in management

Hypoxic Ischemic Encephalopathy.
Pathophysiology & Recent advances in management.

Viraj.
Guide: Dr.Deepak Dwivedi.

Overview.
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Introduction.
Brain physiology.
Definition.
Etiology.
Pathophysiology.
Management.
Neuroprotective strategies.
Summary.

Introduction.
• An important cause of permanent damage to
CNS tissues.
• 20-30% of infants with HIE die in the neonatal
period.
• 33-50% of survivors are left with permanent
neurodevelopmental abnormalities(cerebral
palsy, mental retardation).
NELSON'S TEXTBOOK OF PEDIATRICS.19TH EDITION.

• According to NNPD 2000 data,
– Perinatal asphyxia – responsible for 20% of all
neonatal deaths.
– Manifestations of HIE were seen in approximately
1.5% of all babies.
– Perinatal asphyxia was the commonest cause of
still births accounting for one-third of all such
cases.

Neonatology protocols, The Indian journal of pediatrics.

Brain physiology of a newborn.
• An overall lower cerebral O2 demand when
compared to adults.
• Areas of active neural development that are
associated with either synapse formation or
activation of enzymes required for ion
homeostasis, with considerably increased
cerebral oxidative metabolism.
Avery's diseases of the newborn,9th edition.

• Glucose is the primary source of energy in
cerebral metabolism.
• Capable of utilizing alternative energy
substrates such as ketones, lactate, and free
fatty acids, glucose uptake mechanisms are
underdeveloped.(Cremer et al, Gregoire et al)
• Absence of energy stores makes the brain
dependent on sustained perfusion.

• Vasoautoregulation in response to increased
cerebral blood pressure or flow is relatively
underdeveloped in the newborn.
• The gradual increase in vascularity of the
developing brain leads to the creation of
watershed areas(i.e., areas not well
vascularized).

• Similarities between processes essential for brain
development and those mediating cellular injury.
– An increased density of glutamate receptors.
– An increase in glutataminergic synapses in particular
regions of the immature brain.
– Enhanced accumulation of cytosolic calcium after
activation of the glutamate receptor.

• Proportionately more glutamate receptors in
immature rat brain than mature.(Yager et al).

Terminology.
• Anoxia-Consequences of complete lack of
oxygen as a result of a number of primary
causes.
• Hypoxemia-Decreased arterial concentration
of oxygen.
• Hypoxia-Decreased oxygenation to cells or
organs.
• Ischemia-Blood flow to cells or organs that is
insufficient to maintain their normal function.
Nelson's textbook of pediatrics,19th edition.

Definition.
• An abnormal neurobehavioral state consisting
of decreased level of consciousness and
usually other signs of brainstem and/or motor
dysfunction with objective data to support a
hypoxic ischemic mechanism as the
underlying cause.

Manual of neonatal care.7th edition

Etiology.
• Results when the decrease in cerebral
perfusion is severe enough to overwhelm the
ability of tissue to extract oxygen from blood,
thereby leading to a mismatch cerebral blood
flow and oxidative metabolism.
• Multifactorial.


• Maternal causes:
– Inadequate oxygenation of maternal blood.
– Low maternal blood pressure.
– Inadequate relaxation of the uterus.
– Premature separation of the placenta.
– Impedance to the circulation of blood through the
umbilical cord.

• Placental insufficiency:

• Postnatal:
– Failure of oxygenation.
– Severe anemia.
– Shock.


Pathogenesis.
• Divided arbitrarily into four phases.
– A decrease in cerebral energy and membrane
depolarization.
– A phase of increased release of neurotransmitters
and neuronal damage.
– A period of reperfusion.
– A final phase of irreversible cell death.


Phase I – Decrease in cerebral energy and
membrane depolarization.
• Depression of brain function-Probably a
protective mechanism to preserve energy.
A decrease in brain glucose and ATP.
Activation of anaerobic glycolysis.

Failure of the Na/K ATPase pump.

Decreased diffusion of oxygen and
glucose to the neurons.

Lactate accumulation leading
to tissue acidosis inhibiting
both vascular autoregulation
and phosphofructokinase.


Phase II – Phase of increased release of
neurotransmitters and neuronal damage.
• There is sufficient evidence that excitatory
neurotransmitters play a major role in HI-R
injury.
• Excitotoxicity – excessive glutamatergic
activation that leads to cell energy and death.
(olney, 2003)


Glutamate & its receptors.
• Glutamate - An excitatory neurotransmitter.
• 3 subtypes of receptors.
– N-methyl-D-aspartate (NMDA).
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Plays an important role in normal brain development.
Expression of receptors changes with maturation.
Density is higher in regions of active development.
Different subtypes vary in different regions of the brain at
different gestational ages.

– Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
(AMPA).
– G protein associated metabotropic receptor.

• Activation of any of the three subtypes of
glutamate-activated postsynaptic neuron
receptors leads to an influx of calcium into the
postsynaptic neurons.


Postsynaptic receptor stimulation by
glutamate.
NMDA Receptor
stimulation.

Activation of the
AMPA receptor.

Activation of the
metabotropic
receptor.

Releases the
magnesium block
within the ion
channel.

triggers an influx of
sodium causing
membrane
depolarisation.

Generation of
inositol
triphosphate.

Release of calcium.

• The increase in intracellular calcium sets into
motion an irreversible cascade of events that
leads to cell injury.
• Calcium activates several degradative
enzymes such as phospholipases, proteases,
and endonucleases.


Activated
phospholipases
(phospholipase A2)

Hydrolyze membrane
phospholipid releasing
arachidonic acid.

Increased release of glutamate,
Uncoupling of oxidative
phosphorylation,
inactivation of membrane Na/K
ATPase

Proteases

Cyclooxygenase

Degrade
cytoskeletal &
other proteins.

Production of
arachidonic acid &
prostaglandins.

Generate free radicals
causing lipid membrane
peroxidation.

• Hypoxic ischemic injury also leads to a change
in iron homeostasis.
• It reduces iron usually maintained in non toxic
state “ferric” to toxic “ferrous” form.
• This reacts with oxygen reactive species to
propagate further injury.

Oxidative stress.
• Nitric oxide synthase (NOS)- released during HI-R
injury, acts as a mediator of cell injury.
• NO causes cellular injury by
– Combining with superoxide to form a peroxynitrate
radical that causes lipid peroxidation.
– Generating free radicals by stimulation of COX
activity.
– Direct DNA damage.
– Participating in the neurotransmitter response by
reentering the pre synaptic neuron & further
increasing release of glutamate.

Phases of injury during reperfusion.
• First phase.

– Cerebral energy metabolism restored over 30 mins.
– Resolution of acute cellular hypoxic depolarization &
cell swelling.

• Latent phase.

– Near normal oxidative cerebral metabolism.
– Depressed electroencephalogram and reduced blood
flow.

• Secondary energy failure.

– Inhibition of oxidative phosphorylation.
– Cytotoxic edema leading to delayed seizures.

Cell death.
• Cell death can occur as necrosis or apoptosis
after ischemia.
• A severe insult leads to necrosis, as seen in
the central area of injury.
• A longer duration of less severe injury may
lead to apoptosis, as seen in the penumbra.

• In the immature brain, a third pathologic form of
injury has been described : The apoptoticnecrotic continuum.(Portera-cailliau et al).
• This particular pattern may represent the
predominant form of injury.(Northington et al,2001a,2001b).
• There is prolonged period of delayed cell death
due to apoptosis.(Nakajima et al 2000,Northington et al 2001a).
• This suggests that there is a prolonged window of
opportunity for interventional strategies.

Management of HIE.
• Secure an appropriate airway & maintain
adequate circulation.
• No consensus regarding the need to treat
cerebral edema aggressively, because its role in
producing neurologic sequelae is debatable.
• Corticosteroids are not beneficial in management
of cerebral edema.
• Controlled hyperventilation and use of
furosemide or mannitol may actually be harmful.
(Collins et al,2001)


• Monitoring of seizure activity and control by
anticonvulsants.
• aEEG or EEG should be used to monitor
subclinical seizure.(Bjorkman et al,2010;Glass et al,2009;Miller
et al,2002d;Van Rooij et al,2010)

• Monitor multiorgan function carefully.
• Maintenance of adequate cerebral perfusion,
use inotropic agents in pts with evidence of
myocardial dysfunction.

• Avoid both systemic hypotension and
hypertension.
• Prevent SIADH.
• Avoid fluid overload.
• Monitor serum glucose and electrolytes
closely.
• Closely monitor body temperature and avoid
hyperthermia.

Transfer to newborn unit.(obtain a cord
gas)

Avoid hyperthermia.
Check vital signs at
regular intervals.
Check blood gases,blood
sugar,hematocrit & sr.calcium
Insert intravenous and central lines.
Consider use of volume expander and
inotropes.
Vitamin K, stomach wash , urine
output monitoring.
Neonatology protocols , Indian journal of pediatrics

Maintain
oxygenation
and
ventilation.
Maintain
adequate
perfusion.

Maintain
normal
glucose
Subsequent
management.

Treat
seizures

Maintain
normal
hematocrit.
Neonatology protocols , Indian journal of paediatrics

Maintain
normal
serum
calcium.

• Those with moderate to severe
encephalopathy should be referred and
transferred to an institution with a
hypothermia program within the first 6 hours
of life.


Strategies for neuroprotection.
• Anticipation and prevention of conditions that
cause HIE constitute the best neuroprotective
strategy.


Issues of neuroprotective measures.
• Early identification of infants with a
moderately severe insult is necessary.
• Difficult to assess the degree of
encephalopathy initially.
• Interruption of the injurious events may also
simultaneously affect normal development
processes.


• Route and timing of intervention.
• Asphyxia in neonates is often associated with
multiorgan dysfunction, which can affect the
pharmacokinetics of drug therapy.
• Side effects can include hypotension and
cardiac depression, exacerbating the initial
injury by reducing cerebral perfusion
pressure.

• Strategies exert effect at different stages of
the cascade of events.
• These include
– To reduce depletion of ATP stores.
– To reduce membrane depolarization.
– To inhibit glutamate release.
– To inhibit accumulation of intracellular calcium.


– To block glutamate responsive NMDA & AMPA
receptors.
– To prevent release of degradative enzymes.
– To sequester free radicals.
– To use thrombolytic enzymes.
– To prevent the reperfusion injury by inhibition of
xanthine oxidase.


Maintaining energy stores.
• Prevention of depletion of cerebral energy
stores is a strategy that can be utilized in cases
in which injury is anticipated.
• Seizures and conditions that exacerbate
energy depletion such as hyperthermia, be
avoided in cases of HI-R injury.


Hypothermia.
• The most exciting and viable neuroprotective
strategies.
• Cerebral metabolism after the initial phase of
energy failure during asphyxia may recover in
a latent phase but then deteriorate in a
secondary phase of brain injury 6 to 15 hrs
later.

• Moderate hypothermia established within 30
minutes after the HI-R injury is
neuroprotective.
• Inhibits early adverse events as well as later
events such as secondary energy failure and
apoptosis. (Coimbra and Wieloch,1994;Colbourne and
Corbett,1994;Sirimanne et al,1996;Edwards et al,1995;Haaland et
al,1997;Thoresen et al,1995,1996;Tooley et al,2003)

• Possible mechanisms.
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Inhibition of glutamate release.
Decreased metabolism & energy conservation.
Decreased metabolic acidosis.
Decreased free radical generation.
Prevention of energy failure and apoptosis.
Inhibition of effects of adhesion molecules at the
microvascular level.
– Inhibits the break down of the blood brain barrier and
reducing brain edema.

• Some studies indicate that hypothermia
delays but does not prevent the cellular or
vascular outcome of HIE.
• However, even delaying onset of damage can
be helpful in prolonging the therapeutic
window for other therapies to take effect.


• First reported in the therapy of infants after
perinatal asphyxia(Westin et al,1959).
• Selective head cooling – mild hypothermia
induced by application of a water cooled coil to
the infant’s head, thereby lowering the cranial
temperature to 34.5 degree celsius for 72 hours
within 2 to 5 hours after the injury, rectal
temperature was maintained upto 35.7 degree
celsius was safe with minimal systemic toxicity.
(Gunn et al,1998)


• Both selective head cooling and whole body
cooling have demonstrated benefit in those
with moderate encephalopathy.(Azzopardi et
al,2009;Eicher et al,2005;Gluckman et al,2005;Shankaran et al,2005).

• The therapeutic benefit on those with severe
encephalopathy differs between the studies.


• In a metaanalysis of 8 trials, hypothermia for
moderate/severe neonatal encephalopathy in
neonates with evidence of perinatal asphyxia
resulted in
– A significant reduction in mortality or major
neurodevelopmental disability to 18 months of
age.
– Statistically significant reductions in mortality.
– Statistically significant reduction in
neurodevelopmental disability in survivors.

• Given these findings and because there are
currently no other effective therapeutic
options, hypothermia is being implemented in
many NICU’s as a neuroprotective strategy for
HIE.(Jacobs et al,2007).


Preconditioning and growth factors.
• The response of neonatal brain to milder
forms of injury can help us learn about
mechanisms that the brain uses to protect
itself from insults.
• Genes upregulated by stress, such as those
that induce growth and differentiation, have
been shown to be neuroprotective in animal
models.(Han and Holtzman,2000)

• Animals treated with sublethal stress are
protected from subsequent insults that would
otherwise be deadly.(Bergeron et al,2000;Sheldon et
al,2007).

• Immature rats exposed to hypoxia have
reduced brain injury following HI that occurs
24 hours after this preconditioning stimulus,
with protection that persists 1 to 3 weeks
later.(Gidday et al,1994;Vannucci et al,1998).

• Injury may only be delayed, and protection
may not be permanent; however, hypoxic
preconditioning does provide long lasting
histological and functional protection for upto
8 weeks.(Gustavsson et al,2005).


• HIF-1α: A neuronal transcription factor that
stabilizes during hypoxia by binding to HIF-1β.
• Following stabilization, it produces a variety of
downstream targets that are neuroprotective,
including insulin-like growth factor-1(IGF-1),
vascular endothelial growth factor(VEGF), and
erythropoietin(EPO).

• Thus HIF-1α activation is a key modulator of
the protection against subsequent HI injury
that is induced by hypoxic preconditioning
(Bergeron et al,2000; Ran et al,2005).


Sheila M. Curristin et al, Disrupted synaptic development in the hypoxic ,PNAS,November 26,2002,vol. 99, no. 24,15729–15734

Erythropoietin (EPO).
• A glycoprotein originally identified for its role
in erythropoiesis.
• EPO & EPO receptors are expressed by a
variety of different cell types in the CNS with
changing patterns during development (Juul et
al,1999).


• Functions include
– Modulation of the inflammatory and immune
responses (Villa et al,2003).
– Vasogenic and proangiogenic effects through its
interaction with VEGF (Chong et al,2002;Wang et
al,2004b), as well as effects on CNS development
and repair.
– key role in neural differentiation and neurogenesis
early in development, promoting neurogenesis in
vitro and in vivo (Shingo et al,2001)

• Post injury treatment protocols with
exogenously administered EPO has a
protective effect in a variety of different
models of brain injury in newborn rodents
with both short- and long- term histological
and biological improvement(Sola et al,2005b).


• A single dose of EPO given immediately after neonatal
HI injury in rats significantly reduces infarct volume
and improves long term spatial memory(Kumral et al,2004).
• A single and multiple dose treatment regimens of EPO
following neonatal focal ischemic stroke in rats
– reduce infarct volume (Sola et al,2005a)
– improve both short term sensorimotor (Chang et al,2005) and
long term cognitive (Gonzalez et al,2009) outcomes,
– but there may be more long lasting behavioral benefit in
female rats (Wen et al,2006).

• EPO treatment initiated 24 hours after
neonatal HI also decreases brain injury (Sun et
al,2005) .

• EPO enhances neurogenesis and directs
multipotential neural stem cells toward a
neuronal cell fate (Gonzalez et al,2007;Shingo et al,2001;Wang
et al,2004b).

• EPO has been shown to enhance neurogenesis
in vivo in the SVZ (subventricular zone) after
stroke in the adult rat (Wang et al,2004b).

• In humans, EPO is safely used for treatment of
anemia in premature infants (Aher and Ohlsson,2006).
• EPO for neuroprotection is given in much
higher doses (1000-5000 U/kg/dose) than for
anemia to enable crossing of the blood brain
barrier with unknown pharmacokinetics in
humans (Chang et al,2005;Demers et al,2005;McPherson &
Juul,2007).

• ELBW infants tolerated doses between 500
and 2500 U/kg/dose (Juul et al,2008), and studies
are ongoing.
• Repeated low dose EPO over the first 2 weeks
of life resulted in a reduction in death or
moderate/severe disability at 18 months of
age (Zhu et al,2009).
• A multicentre trial is currently underway.

VEGF.
• A regulator of angiogenesis and is also
involved in neuronal cell proliferation and
migration (Zachary,2005).
• The endothelial microenvironment establishes
a vascular niche that promotes survival and
proliferation of progenitor cells, which is
tightly coordinated with angiogenesis (Palmer et
al,2000).


• VEGF-A : The most important member of a family
of growth factors.
• Expressed in cortical neurons during early
development, switching to mature glial cells near
vessels during maturation.
• After exposure to hypoxia, there is increased
neuronal and glial expression of VEGF-A,
directing vasularization and stimulating
proliferation of neuronal and nonneuronal cell
types.(Forstreyter et al,2002; Jin et al,2002; Krum and Rosenstein
1998; Mu et al,2003).


• VEGF also has chemotactic effects on
neurogenic zones in the brain, increasing
migration of stem cells during anoxia.(Bagnard et
al,2001;Maurer et al,2003;Yang and Cepko,1996).

• VEGF-knockout mice have severe impairments
in vascularization, neuronal migration and
survival (Raab et al,2004).

• Timing of VEGF administration is very
important.
• In adult ischemia models, I/V VEGF
administered 1 hour after insult increases
blood-brain barrier leakage and lesion size,
but late administration 48 hours after
ischemia enhances angiogenesis and
functional performance.(Zhang et al,2000)

• Both topical and intracerebroventricular
injection reduced infarct volume, and benefit
has been shown in neurodegenerative and
traumatic models of injury as well.(Harrigan et
al,2003; Hayashi et al,1998).

• VEGF over-expression confers direct
neuroprotection resulting from inhibition of
apoptotic pathways.(Zachary,2005).

• Other factors have also shown promise, but given
their role in normal neurodevelopment, the
effects of treatment are not known.
• IGF-1 : Important for growth and maturation of
the fetal brain, as well as differentiation of
oligodendrocyte precursors. (D’Ercole et al,1996).
• Has prosurvival properties that can prevent
perinatal hypoxic and excitotoxic injury, and it is
also effective after intranasal administration.
(Johnston et al,1996; Pang et al,2007; Lin et al,2009).


• Brain derived neurotropic factor : a
neurotrophin that also provides neuroprotection
in neonatal HI.(Cheng et al,1997,1998; Holtzman et al,1996; Husson et
al,2005).

• Prevents spatial learning and memory
impairments after injury, but its effectiveness is
limited by the stage of development.(Cheng et
al,1997,1998; Husson et al,2005).

• Protective in mice when given on postnatal day 5
(P5), it has no effect at later time points and
actually exacerbates excitotoxicity if given on the
day of birth.(Husson et al,2005).

Antioxidants.
• Antioxidant defenses such as superoxide
dismutase, glutathione peroxidase, catalase,
and compounds such as vitamins A,C, and E,
as well as beta- carotene, glutathione, and
ubiquinones scavenge free radicals (FRs)
under normal conditions.


• Damage occurs when there is an imbalance
between their generation and uptake (Fridovich,1997).
• Following HI, there is an increase in superoxide
and hydroxyl radical production and rapid
depletion of antioxidant stores, which leads to
cell membrane damage, excitotoxic energy
depletion, cytosolic calcium accumulation, and
activation of pro-apoptotic genes that cause
damage to cellular components and result in cell
death (Taylor et al,1999)

• Strategies to reduce oxidative damage to the
neonate,
– Reactive oxygen species scavengers (ROS),
– Lipid peroxidation inhibitors,
– FR reducers,
– Nitric oxide synthase (NOS) inhibitors.


• Initial results in premature infants treated
with inhaled NO for prevention of
bronchopulmonary dysplasia show reductions
in ultrasound diagnosed brain injury and
improvements in neurodevelopmental
outcomes at 2 years of age, but long term
results are still pending.(Ballard et al,2006; Schreiber et
al,2003).


• Melatonin: A direct scavenger of ROS and NO.
• Provide long lasting neuroprotection in
experimental HI and focal cerebral ischemic
injury, and human neonates treated with
were found to have decreased
proinflammatory cytokines.(Carloni et al,2008; Gitto et
al,2004,2005; Koh,2008).


• Allopurinol: Early allopurinol in asphyxiated
infants improved short term
neurodevelopmental outcomes and
decreased NO levels after administration.
• There may only be a brief window for benefit,
because no improvement in long term
outcomes was seen with later treatment after
birth asphyxia.(Benders et al,2006).

• Deferoxamine (DFO) : An iron chelator.
• Decreases FR production by binding with iron
and decreasing the production of OH-.
• Also stabilizes HIF-1α to produce its
downstream products VEGF and EPO.(Hamrick et
al,2005;Mu et al,2005).


• N-Acetylcysteine (NAC) : a glutathione
precursor and FR scavenger that attenuates
LPS induced white matter injury in newborn
rats.(Aruoma et al,1989;Paintlia et al,2004).
• Results for other anti oxidant compounds,
such as vitamin E, have been inconclusive.(Brion
et al,2003).


Antiexcitotoxicity.
• Dizocilpine(MK801) : A noncompetitive NMDA
receptor antagonist.
• Memantine : a low affinity noncompetitive
NMDA receptor antagonist.
• Topiramate : an AMPA-kainate receptor
antagonist.
• Magnesium sulfate : NMDA receptor
blockade.

Cell death inhibitors.
• Apoptosis and cleavage and activation of
caspase-3 are responsible for more of the cell
death that occurs in delayed phases of injury
and neurodegeneration.(Hu et al,2000).
• MDL 28710 and M826: calpain or caspase-3
inhibitor.
• 17-β estradiol.
• 3-amino benzamide: PARP-1 inhibitor.

Stem cell therapy.
• Neural stem cells: multipotent precursors, self
renew and differentiate into a variety of
neuronal and non neuronal cell types in the
CNS.
• Reside in neurogenic zones throughout life,
such as the SVZ and the dentate gyrus of the
hippocampus.


• Promote regeneration, angiogenesis, and
neuronal cell survival in both rodent and
primate models, and nonneuronal progeny
inhibit inflammation and scar formation.(Imitola
et al,2004; Mueller et al,2006).


Combination therapies.
• Provide more long lasting neuroprotection,
salvaging the brain from severe injury and
deficits while also enhancing repair and
regeneration, possibly involving additive, if
not synergistic, protection.


•
•
•
•

Therapeutic hypothermia.
Xenon – an NMDA antagonist.
N-Acetyl Cysteine.
MK-801.


Summary.
• 33-50% of survivors are left with permanent
neurodevelopmental abnormalities.
• Similarities between processes essential for
brain development and those mediating
cellular injury.
• Excitotoxicity plays a major role in HI-R injury.
• aEEG or EEG should be used to monitor
subclinical seizure.

• Avoid both systemic hypotension and
hypertension.
• Anticipation and prevention of conditions that
cause HIE constitute the best neuroprotective
strategy.
• Hypothermia-The most exciting and viable
neuroprotective strategies.
• Newer modalities are still under research and
need more studies to confirm their
effectiveness.

HIE-Pathophysiology & recent advances in management

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