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

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. 2001.

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

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.

Supportive Management

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.

Supportive Management

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.

Supportive Management

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

• Calcium and magnesium levels should be monitored.

Snyder ,et al., 2004.

Supportive Management

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

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.

Mies ,et al., 1990.

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.

• cooling associated with many side effects.

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.

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.

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.

Trifiletti,et al 1992.

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 resuscitation

• The realization that hypoxia-

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