Hypoxic Ischemic Encephalopathy Updates in Management

Hypoxic Ischemic Encephalopathy

Updates in Management

Mohamed Khashaba, MD

Professor Of Pediatrics & neonatologyHead 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 found that the

PMR was 34/1000 births

• Is mainly due to asphyxia (44%)

and prematurity (21%)

Campbell,et al. 2004

44

21

35

Asphyxia

Prematurity

Other causes

• 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

Disease or ConditionNo. of deaths in

2004 (000s) No. (%) preventable

(000s)

Asphyxia 11758 (49.1)

Prematurity 12763 (49.6)

Sepsis / pneumonia

167100 (59.9)

Tetanus 6944 (64.1)

Diarrhea 213 (15.9)

Congenital disorders

522 (4.2)

Other 331 (2.1)

Total 1401706 (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.

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.

Primary Cell Death

Data Of NEAA Role

• Specific glutamate antagonists prevent

hypoxic cell damage.

• Topography of neuronal death is

similar

to glutamate synthesis distribution

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

Primary Cell Death

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 families

Ladecola ,et al 2001

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




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




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. 2001.


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.


2. Post resuscitation management . a) Cardio-respiratory support:• Avoid hypotension and hypoperfusion.

• Adequate oxygenation (PaO2 60–90 mmHg).

Luc Cornette et al, 2001.

Avoid CO2 disturbancesSteal phenomenon

• Decrease blood flow to areas of

reversible ischemia surrounding infarcted areas due to vc by hypercarbia.


2. 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 Cornette et 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.


2. 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.


2. Post resuscitation management . d) Additional support measures:• Observation of coagulation profile.

• Calcium and magnesium levels should be monitored.

Snyder ,et al., 2004.


2. 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




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.


1- Brain cooling: Mechanism of action:• Hypothermia reduces disruption to

the blood–brain barrier, thereby reducing edema formation .

Clifton . 2004.


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.


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.


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.


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.

Mies ,et al., 1990.


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.

• cooling associated with many side effects.


cooling cap.


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.


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.


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.

Nelson et al., 1995.

• 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.


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.


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.


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.

Trifiletti,et al 1992.


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.


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 resuscitation

• The realization that hypoxia-

ischemia leads to delayed cellular injury gives new motivation to research of post natal therapy

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Hypoxic Ischemic Encephalopathy Updates in Management