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Hypoxic Ischemic


Updates in Management

Mohamed Khashaba, MD

Professor Of Pediatrics & neonatology

Head of NICU
• 1. Stress on the importace of NHIE.
• 2. Throw a light on updates of
diagnosis and management.
Neonatal Encephalopathy

• A clinical syndrome of disturbed

neurologic function in fullterm

newborn that may be causally

related to hypoxia/ischemia
Neonatal HIE

• Clinical disturbance of brain


that may follow hypoxia/ischemia.

Sarnat ,et al. 1976.

Magnitude of the Problem

In Egypt demographic and
health survey (EDHS) 2000 21
found that the PMR was 44 Asphyxia
34/1000 births Prematurity
Other causes

• Is mainly due to asphyxia

(44%) and prematurity (21%)
• Child health and survival in
the Eastern Mediterranean

Bhutta ZA, Belgaumi A, Abdur Rab

M, Karrar Z, Khashaba M, Mouane

BMJ. 2006 Oct 21;333(7573):839-42.

Distribution of neonatal deaths from
specific causes and the proportion that
are preventable

No. of deaths in No. (%) preventable

Disease or Condition
2004 (000s) (000s)

Asphyxia 117 58 (49.1)

Prematurity 127 63 (49.6)
Sepsis / 167 100 (59.9)
Tetanus 69 44 (64.1)
Diarrhea 21 3 (15.9)
Congenital 52 2 (4.2)
Other 33 1 (2.1)
Total 1401 706 (50.4)
Zulfiqar, et al. 2006.
II. Incidence:
*1-1.5 % in general
9% in babies< 36 weeks G.A.
0.5 % in babies > 36 weeks
*Average 20 % of cases of perinatal

*Increased incidence in compromised

fetuses: IUGR, breech, post term, IDM,

• Normally PaO2 is low in the fetus.

• HIE occurs primarily as a


to hypoperfusion.
• Initially, the fetus compensate
asphyxia by increasing cardiac
output and blood flow to all organs.
Jensen ,et al., 1996

• As hypoxia becomes greater, the

fetus redistributes blood flow to
the vital organs at the expense of
other organs.

Williams ,et al 1993

• If hypoxia is prolonged, compensation

mechanism fails.

• Myocardial dysfunction leads to


and cerebral ischemia.

Williams,et al., 1993

Pressure-Passive Cerebral
• Loss of cerebral blood flow

autoregulation 2ry to hypoxia and

• Hypoxic-ischemic injury has a
biphasic pattern:
- primary cell death
- secondary cell

The World Health Report 2005

Primary Cell Death

• Occur during the period of hypoxia-

ischemia and the immediate phase of

Raff, et al., 1992.
Primary Cell Death
Cellular energy failure:

• Anaerobic glycolysis  lactic acid

accumulation  loss of auto regulation

Volpe. 2001

• Failure of ATPase dependant ions channels

Influx of Na+ and Ca2+ ions

Volpe. 2001
Primary Cell Death

• Energy failure impair glutamate uptake 


cellular accumulation of glutamate  tonic


stimulation of post synaptic EAA receptors.

• EAA over activation  increase


calcium and sodium cell swelling.

Grow, et al. 2002.
Data Of NEAA Role

• Specific glutamate antagonists


hypoxic cell damage.

• Topography of neuronal death is


to glutamate synthesis distribution

Primary Cell Death
Free radicals accumulation:

• Asphyxia  incomplete O2 reduction

Free radicle production

• Radicals are highly reactive with

polyunsaturated fatty acids of the
brain i.e arachidonic acid.
Perkin ,et al 1999.

• They perioxidize cell membranes,

alter the blood-brain barrier.
Jacinto et al, 2001.
Primary Cell Death
Accumulation of cytosolic calcium:
• Increase intracellure calcium  activation of
phospholipase , endonucleases, proteases .

• Activation of phospholipase  generate

arachidonic acid, inosiltol-1,4,5 triphosphate
 calcium release from ER.

• Proteases and endoneucleases  damage

cytoskeletal proteins and DNA.

Grow, et al., 2002.

Primary Cell Death
Increase Nitric oxide production

• NO react with oxygen free radical

super oxide anion (O2-) peroxynitrate

• Inhibition of glycolytic substance

enzymes by nitrosylation induction
of DNA damage.

Grow, et al. 2002

Secondary Cell Death

• Occurs hours or days after the initial


• Damaging process occur through

Apoptosis (programmed cell death)

• Key players in the neuronal apoptosis

Bcl-2, Apaf-1, and caspase gene
Secondary Cell Death

• The primary role of the Bcl-2 family

involve formation of pores and
mitochondrial membrane rupture by
pro-apoptotic Bcl-2 members.
Yuan, et al 2000.

• Some of the Caspase enzymes are

responsible for cleaving genomic DNA
into ordered fragments characteristics
of apoptosis.
Updates in Diagnosis
• 1. Magnetic Resonance
• 2. Cerebral Function Monitoring.
Management of Asphyxiated

prevention of asphyxia supportive management

New Neuroprotective
Management of Asphyxiated

prevention of asphyxia supportive


New Neuroprotective approach

Prevention of Intrauterine

• Proper antenatal care ,proper

identification and management of the
fetus who subjected to or likely to
experience asphyxia.

• Proper resuscitation in the delivery


Management of Asphyxiated

prevention of asphyxia supportive


New Neuroprotective
Supportive Management

1. Management in the delivery

a) Oxygen requirement
It is better to avoid 100% O2 during

B) oxidized glutathione (marker of

oxidative stress ),is found to be
higher in infant resuscitated by 100%
O2 than infant resuscitated by room
Vento et al.
Supportive Management

1. Management in the delivery

b) Temperature in the delivery room :
Hyperthermia or hypothermia
should be avoided during
resuscitation and transport of
asphyxiated infant.
Gunn, et al, 2001.
Supportive Management

• Post resuscitation management .

a) Cardio-respiratory support:
• Avoid hypotension and hypoperfusion.

• Adequate oxygenation (PaO2 60–90


Luc Cornette
et al, 2001.
Avoid CO2 disturbances
Steal phenomenon

• Decrease blood flow to areas of

reversible ischemia surrounding
infarcted areas due to vc by
Supportive Management

• Post resuscitation management .

b) Blood pressure and fluids:

• Close monitoring of blood pressure.
• Avoid overload hypoxic–ischemic newborns
• .
• Avoid dehydration as infant usually
maintained in restrictive fluid intake

. Luc Cornetteet al, 2001


• Monitoring& supporting blood pressure

• Inotrops (dopamine) may be required.

• Volume expanders (hazard of overload)

Cerebral Edema
• Intracranial pressure may be elevated
• Cerebral perfusion pressure remains
• Measures to reduce edema lack an effect
on outcome.

• 72% of fits in the first 24 hrs

• Lead to under-perfusion or under
oxygenation of excited cells.
Supportive Management

• Post resuscitation management .

c) control of seizers:

• Drugs given only if seizers detected


• Barbiturates is preferred as it decrease

central nervous system metabolic rate,
reduce post ischemic calcium entry, and
scavenge free radicals

Evans,et al., 2000.

Supportive Management

1. Post resuscitation management .

d) Additional support measures:
• Observation of coagulation profile.

• Calcium and magnesium levels should be


Snyder ,et al., 2004.

Supportive Management

1. Post resuscitation management .

d) Additional support measures:
• Maintain blood glucose level between
75-100 mg/dl.
Volpe. 2001.

• Parents should be informed about infant

case and allowed to ask questions
Discussion with parents
• Should be frank and trustful.
• Discuss possible sequelae
• Prepare for eventual withdrawal of life
support if decided
Management of Asphyxiated

prevention of asphyxia supportive management

New Neuroprotective
Neuroprotective Approach:

1- Brain cooling:
Mechanism of action:
• Cerebral metabolism is reduced by 5 -
7% for each degree centigrade
reduction in temperature
Erecinska , et al, 2003.

• Reduce the duration of seizures

Thoresen , et
al., 2003.
Neuroprotective Approach:

1- Brain cooling:
Mechanism of action:
• Hypothermia reduces disruption
to the blood–brain barrier,
thereby reducing edema
formation .

Clifton . 2004.
:Neuroprotective Approach

1- Brain cooling:
Mechanism of action:
• Hypothermia Reduce apoptosis,
reduce production of the free radical
nitric oxide, and reduce excitatory
amino acids.

Thoresen ,et al., 1997.

:Neuroprotective Approach

1- Brain cooling:
Adverse effects of hypothermia:
• Impairment of myocardial
Levene, 1993.
• Shift the oxygen dissociation curve of
blood to the left .
Edwards, et al., 1993.
• Cooling also impairs clotting.
• Disturbance of acid base balance.
Levene, 1993.
:Neuroprotective Approach
1- Brain cooling:
Optimal brain temperature to achieve
neuroprotection :
• Rectal T 34.5°C for 72 h of selective head
cooling in term infants was found to
decrease morbidity .
• Another randomized clinical trial of 48 h
whole body cooling with rectal T 33°C also
was successful .
Marianne Thoresen et al., 2005.
:Neuroprotective Approach

1- Brain cooling:
Difficulties facing establishing clinical
• Selection of cases in the first few hours
after birth is difficult.
Vries, et al., 2005.
• The need for rapid transfer of the infant
to specialized centre.
• Accurate data about optimal dose and
duration are incomplete.
:Neuroprotective Approach

1- Brain cooling:
Difficulties facing establishing clinical
• The time delay before treatment is still
• it is not clear whether total body
hypothermia or selective head cooling is
Mies et al., 1990.

:Neuroprotective Approach

cooling cap.
:Neuroprotective Approach

2 -Magnesium Sulfate :
mechanism of action:
• Inhibition of the NMDA receptor.
• Anticonvulsant properties .
• Magnesium also block the activation of
NO-synthase after cerebral ischemia.
Garnier ,et al.,
:Neuroprotective Approach

2 -Magnesium Sulfate :
Side effects:
• MgSO4 acts as a calcium-channel
blocker, it may cause hypotension,
bradycardia .
• MgSO4 acts as a neuromuscular blocking
agent that cause transient respiratory
muscle paralysis and apnea.
Levene, 1995.
:Neuroprotective Approach

2 -Magnesium Sulfate :
Clinical trials
A retrospective analysis carried out by
Nelson and Grether , in a 155, 636
infants, showed that antepartum
application of magnesium lowered the
incidence of cerebral palsy in newborns
weighing less than 1500g.
• Excitatory amino acids and
magnesium sulfate in
neonatal asphyxia.
Khashaba MT, Shouman BO,
Shaltout AA, Al-Marsafawy HM,
Abdel-Aziz MM, Patel K, Aly H.
Brain Dev. 2006 Jul;28(6):375-9. Epub 2006 Mar
:Neuroprotective Approach

3 -Oxygen-free Radical Inhibitors

• Deferoxamine, Lazeroids are still under
expermental trails.
• Allopurinol: In a small randomized trial
involving severely asphyxiated
neonates, a beneficial effect of high-
dose allopurinol (40 mg/kg) is observed.

Berger, et al., 1999.

:Neuroprotective Approach

4 -Calcium Channel Blockers:

Still under experimental trials.

5 -Sodium Channel Blockers:

may have a role in maintenance of normal
CBF (autoregulation).
Parfenova, et al .,1996
Complement component 9 activation,
consumption, and neuronal
deposition in the post-hypoxic-ishemic
central nervous system of Human
newborn infants

Seth j. Schultz, Aly H,Hasanen B, Khashaba

M, et al.
Neuroscience Letters 378 (2005)1-6.
• Neurodevelopmental Outcome in Full
Term Infants With Neonatal Asphyxia:
Relation to Complent 9.

• Khashaba M., El-Ayouty M., aly H.,Soliman O.,

Hasaneen B.

Child Neuropsychiatry Vol-1(1)Sep.2004

• Complement component 9
activation, consumption, and
neuronal deposition in the post-
hypoxic-ishemic central nervous
system of human newborn infants.
Schultz S, Hany Aly, Hasanen B, Khashaba
M, Sheron L, Bendon R, Gordon L ,Feldhof
P, Lassiter H.
Neuroscience Letters 378 (2005)1-6.
• IL-1beta, IL-6 and TNF-alpha and
outcomes of neonatal hypoxic
ischemic encephalopathy.
Aly H, Khashaba MT, El-Ayouty M,
El- Sayed O, Hasanein BM.

Brain Dev. 2006 Apr;28(3):178-82. Epub 2005 Sep 21.

:Neuroprotective approach

6-Neuronal Growth Factors :

• fibroblast growth factors (FGF-1)
show neuroprotection in experimental
Kirschner ,et al 1995.

• Insulin like growth factor I (IGF-I)

also had neuronal rescue effect after
hypoxic-ischemic injury in fetal lambs.
Johnston ,et al., 1996.
:Neuroprotective approach

6-Neuronal Growth Factors :

• growth hormone (GH)
Show neuroprotection in unilateral
carotid ligation/hypoxia model neonatal
• Nerve growth factor (NGF)
NGF may exert its effect by inhibiting
Gustafson ,et al., 1999.
:Neuroprotective Approach

7-Nitric Oxide Synthase

• In a model of hypothermic
circulatory arrest using of 7-
nitroindazole, was effective at
reducing apoptosis.
• Specific inhibition of neuronal and
nitric oxide synthase remains an
experimental strategy.
:Neuroprotective Approach

8- N-Methyl-D-aspartate Receptor
• The use of NMDA-receptor antagonists
such as ketamine, cerestat,
dextromethorphan, have been proven
successful in animal studies,
• These substances decrease
intracellular calcium accumulation .
• their use as neuroprotective agents in
neonate is not currently recommended.
Bokesch PM ,et al., 2000.
:Neuroprotective Approach

11- Inhibition of Caspase Enzymes:

• Caspase enzymes play a key role in
• In the developing rat brain,
caspase inhibition interrupts cell
death and provides a prolonged
therapeutic window after hypoxic–
ischemic insults.
Nicholson, et al., 1997.
Long term sequelae

1. Stage III: most survivors are

2. Persistence of moderate encephalo
pathy beyond 5 days
3. Interictal background EEG

• We must consider the magnitude of

perinatal and neonatal asphyxia in
order to develop programs that will
reduce avoidable neonatal deaths
more quickly.
• The corner stone for HIE
management is prevention of
perinatal asphyxia through
effective antenatal care and
• The realization that hypoxia-
ischemia leads to delayed cellular
injury gives new motivation to
research of post natal therapy