Anda di halaman 1dari 67

Hypoxic Ischemic

Encephalopathy

Updates in Management

Mohamed Khashaba, MD

Professor Of Pediatrics & neonatology


Head of NICU
MANSOURA UNIVERSITY
Objectives
• 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


function

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
35

• Is mainly due to asphyxia


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

Bhutta ZA, Belgaumi A, Abdur Rab


M, Karrar Z, Khashaba M, Mouane
N.

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)
pneumonia
Tetanus 69 44 (64.1)
Diarrhea 21 3 (15.9)
Congenital 52 2 (4.2)
disorders
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
G.A.
*Average 20 % of cases of perinatal
death

*Increased incidence in compromised


ITM.
fetuses: IUGR, breech, post term, IDM,
Pathogenesis

• Normally PaO2 is low in the fetus.

• HIE occurs primarily as a


consequence

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


hypotension

and cerebral ischemia.

Williams,et al., 1993


Pressure-Passive Cerebral
Circulation
• Loss of cerebral blood flow

autoregulation 2ry to hypoxia and

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

The World Health Report 2005


Primary Cell Death

• Occur during the period of hypoxia-

ischemia and the immediate phase of

reperfusion.
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
Excitotoxicty:

• Energy failure impair glutamate uptake 


extra

cellular accumulation of glutamate  tonic


over-

stimulation of post synaptic EAA receptors.

• EAA over activation  increase


intracellular

calcium and sodium cell swelling.


Grow, et al. 2002.
Data Of NEAA Role

• Specific glutamate antagonists


prevent

hypoxic cell damage.

• Topography of neuronal death is


similar

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
(ONOO-).

• 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


insult.

• Damaging process occur through


Apoptosis (programmed cell death)

• Key players in the neuronal apoptosis


are
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.
Nicholson,2002
Updates in Diagnosis
• 1. Magnetic Resonance
Spectroscopy.
• 2. Cerebral Function Monitoring.
Management of Asphyxiated
Babies

prevention of asphyxia supportive management

New Neuroprotective
approach
Management of Asphyxiated
Babies

prevention of asphyxia supportive


management

New Neuroprotective approach


Prevention of Intrauterine
Asphyxia

• Proper antenatal care ,proper


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

• Proper resuscitation in the delivery


room.
.

Volpe,2001
Management of Asphyxiated
Babies

prevention of asphyxia supportive


management

New Neuroprotective
approach
Supportive Management

1. Management in the delivery


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

B) oxidized glutathione (marker of


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

1. Management in the delivery


room.
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


mmHg).

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
hypercarbia.
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


Perfusion

• 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
normal.
• Measures to reduce edema lack an effect
on outcome.
Seizures

• 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


clinically.

• 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


monitored.

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
Babies

prevention of asphyxia supportive management

New Neuroprotective
approach
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
contractility.
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
trials:
• 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
trials:
• The time delay before treatment is still
unclear
• it is not clear whether total body
hypothermia or selective head cooling is
better.
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.,
2002.
: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
20.
: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
trials
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
rats.
• Nerve growth factor (NGF)
NGF may exert its effect by inhibiting
apoptosis.
Gustafson ,et al., 1999.
:Neuroprotective Approach

7-Nitric Oxide Synthase


Inhibitors:
• 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
Antagonists:
• 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
apoptosis.
• 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


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

• 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