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Hypoxic-Ischemic Encephalopathy in the Term Infant Jeffrey M Perlman MB Professor of Pediatrics Weill Medical College Cornell Medical Center New York. Background.

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slide1

Hypoxic-Ischemic Encephalopathy

in the Term Infant

Jeffrey M Perlman MB

Professor of Pediatrics

Weill Medical College

Cornell Medical Center

New York

background
Background
  • Hypoxic-ischemic brain injury that occurs during the perinatal period remains the most prominent cause of neonatal mortality and long term neurologic morbidity often referred to as cerebral palsy.
  • It is noted in approximately 1 to 2 per 1000 deliveries.
  • An understanding of the pathogenesis of injury is critical prior to the implementation of targeted interventions.
outline
Outline
  • Pathogenesis
  • Adaptative fetal mechanisms
  • Identification of High risk Infants
  • Treatment strategies

Delivery room

- room air versus 100% O2

Beyond the delivery room

- supportive care

- neuroprotective strategies

pathogenesis
Pathogenesis

Impaired cerebral blood flow (CBF) is the principal pathogenetic mechanism underlying most of the neuropathology attributed to perinatal brain injury. It is most likely to occur as a consequence of interruption of placental blood flow and gas exchange; a state that is referred to as asphyxia.

definitions
Definitions
  • Hypoxia - refers to an abnormal reduction in oxygen delivery to the tissue
  • Ischemia - refers to a reduction in blood flow to the tissue
  • Asphyxia - refers to progressive hypoxia, hypercarbia and acidosis. However the biochemical definition of what constitutes asphyxia is imprecise - a cord pH < 7.00 is defined as pathologic or severe fetal acidemia.
characteristics of hypoxic ischemic brain damage
Characteristics of Hypoxic-Ischemic Brain Damage
  • Hypoxic-ischemic brain injury is an evolving process that begins during the insult and extends into a recovery period - reperfusion period
  • Tissue injury takes the form of :

Necrosis - characterized by tissue swelling, membrane

disruption and an inflammatory cellular response or

Apoptosis “programmed cell death” characterized by

cellular and nuclear shrinkage, chromatin condensation

and DNA fragmentation.

  • A severe insult results in necrosis and a less severe and prolonged insult in apoptosis
slide7
Electron microscopic images of dying neurons in neocortex from an infant rat 48 hours after hypoxia-ischemia

Necrotic neuron with chromatin

dispersed into numerous small

irregular shaped structures and

disrupted nuclear and cytoplasmic

membranes

Apoptotic neuron with one

large apoptotic body including

condensed chromatin

slide8

Pathogenesis of Hypoxic-Ischemic Cerebral Injury

Interruption of Placental Blood Flow

Acute

Intermittent

Hypoxia-Ischemia

Resuscitation

In-utero

Postnatal

Reperfusion Injury

effects of hypoxia ischemia on carbohydrate and energy metabolism anaerobic glycolysis
Effects of Hypoxia-Ischemia on Carbohydrate and Energy Metabolism-Anaerobic Glycolysis
  •  Brain Glycogen
  •  Lactate production
  •  Phosphocreatine
  •  Brain Glucose
  •  ATP
  • Tissue acidosis
adenosine triphosphate atp
Adenosine Triphosphate (ATP)
  • Critical regulator of cell function because of its role in energy transformation.
  • One major function is to preserve ionic gradients across plasma and intracellular membranes, i.e., Na , K , Ca  
  • Ionic pumping utilizes 50-60% of total cellular expenditure
slide11

Ischemia

Anaerobic Glycolysis

 PCr

 ATP

 Lactate

[Na+]out

[K+] out

[Ca++] in

deleterious effects of calcium in hypoxia ischemia
Deleterious Effects of Calcium in Hypoxia-Ischemia
  • Activates phospholipases membrane injury
  • Activates proteases cytoskeleton degraded
  • Activates nucleases DNA breakdown
  • Uncouples oxidative phosphorylation  ATP
  •  neurotransmitter release i.e. glutamate
  • Activates NOS generates nitric oxide
additional mediators of cell death during and following hypoxia ischemia hi
Additional Mediators of Cell Death During and Following Hypoxia-Ischemia (HI)
  • Free radicals

- highly reactive compounds

- can react with certain cellular constituents

e.g. membrane lipids generating more

radicals and thus a chain reaction with

irreversible biochemical injury.

  • Glutamate

- Excitatory amino acid acts on NMDA

receptors to facilitate intracellular Ca++

entry and delayed cell death

- Glutamate accumulates during HI in part

because of  reuptake that requires ATP

slide14

Potential Mechanisms of Injury Following Hypoxia-Ischemia

HYPOXIA-ISCHEMIA

ANAEROBIC GLYCOGLYSIS

ATP

ADENOSINE

GLUTAMATE

LACTATE

NMDA RECEPTOR

HYPOXANTHINE

INTRACELLULAR Ca+

XANTHINE

OXIDASE

ACTIVATES

NOS

ACTIVATES LIPASES

XANTHINE

FREE FATTY ACIDS

O2

NITRIC OXIDE

O2

FREE RADICALS FREE RADICALS FREE RADICALS

slide15

Calcium

NOS

Nitric Oxide

Peroxynitrite

Mitochondria

Cytochrome C

Caspace

Energy Failure

DNA

Fragmentation

Nuclear /Cytoplasmic

Breakdown

Apoptosis

Necrosis

delayed injury reperfusion injury
Delayed Injury - Reperfusion Injury
  • Following resuscitation cerebral oxygenation and

perfusion is restored. During this initial recovery

phase, the concentration of the phosphorus

metabolites (ATP) and intracellular pH returns

to baseline.

  • However the process of cerebral energy failure

recurs from 6 to 48 hours later in a secondary

phase of injury. This phase is characterized by

a decrease in phosphocreatinine although the

intracellular pH remains normal. Moreover this

phase occurs despite stable cardio-respiratory

status

From Lorek et al Pediatr Res 1994

slide17

Pathogenesis of Hypoxic-Ischemic Cerebral Injury

Interruption of Placental Blood Flow

Acute

Intermittent

Hypoxia-Ischemia

Resuscitation

In-utero

Postnatal

Reperfusion Injury

mechanisms of reperfusion injury
Mechanisms of Reperfusion Injury
  • The mechanisms of secondary energy failure likely secondary to extended reactions from the primary insults e.g. calcium influx, excitatory neurotoxicity, free radicals and nitric oxide formation adversely alters mitochondrial function.
  • Recent evidence suggests that circulatory and endogenous inflammatory cells/mediators also contribute to the ongoing injury.
  • These processes result in apoptotic cell death.
slide19

Infection and/or the fetal inflammatory

response as a potential contributing factor

to brain injury during hypoxia-ischemia

conclusions
CONCLUSIONS
  • In infants exposed to chorioamnionitis, there was a spectrum of abnormalities in the neurological exam from normal, to transient hypotonia, to HIE
  • IL-6, IL-8 and RANTES were significantly elevated in all infants with Chorio as compared to controls

- IL6 at 6 hours were correlated with hypotonia

by Modified Dubowitz Scores

- IL6, IL8 and RANTES at 6 hrs were highest in

infants that developed HIE and/or seizures

speculation
SPECULATION

Chorioamnionitis Hypotonia HIE / Seizures

CYTOKINES

slide26

Potential Mechanisms of Injury Following Hypoxia-Ischemia

HYPOXIA-ISCHEMIA

ANAEROBIC GLYCOGLYSIS

ATP

ADENOSINE

GLUTAMATE

LACTATE

NMDA RECEPTOR

HYPOXANTHINE

INTRACELLULAR Ca+

XANTHINE

OXIDASE

ACTIVATES

NOS

ACTIVATES LIPASES

XANTHINE

FREE FATTY ACIDS

O2

NITRIC OXIDE

O2

FREE RADICALS FREE RADICALS FREE RADICALS

slide27

HYPOXIA-ISCHEMIA

ANAEROBIC GLYCOGLYSIS

ATP

ADENOSINE

GLUTAMATE

LACTATE

IL-

TNF-

NMDA RECEPTOR

HYPOXANTHINE

IL-

TNF-

Interferon 

INTRACELLULAR Ca+

XANTHINE

OXIDASE

ACTIVATES

NOS

ACTIVATES LIPASES

XANTHINE

FREE FATTY ACIDS

O2

NITRIC OXIDE

O2

FREE RADICALS FREE RADICALS FREE RADICALS

foundation fact

Foundation Fact

Although interference in placental blood flow and consequently gas exchange is fairly common, residual neurologic sequelae are infrequent and are more likely to occur when the asphyxial event is severe.

slide29

WHY?

The fetus immediately adapts to an asphyxial event to preserve cerebral blood flow and oxygen delivery. This adaptation includes both circulatory and non circulatory responses.

cardiovascular responses to asphyxia

ASPHYXIA (PaO2, PaCO2,pH)

Redistribution of Cardiac Output

Cerebral, Coronary, Adrenal Renal, Intestinal

Blood Flow Blood Flow

Ongoing Asphyxia

Cardiac Output

Cerebral Blood Flow

CARDIOVASCULAR RESPONSES TO ASPHYXIA
adaptive mechanisms associated with asphyxia to maintain cerebral perfusion
ADAPTIVE MECHANISMS ASSOCIATED WITH ASPHYXIA TO MAINTAIN CEREBRAL PERFUSION
  • Circulatory Responses
  • Non-circulatory Responses
non circulatory responses factor contributing to neuronal preservation
NON-CIRCULATORY RESPONSES FACTOR CONTRIBUTING TO NEURONAL PRESERVATION
  • Slower depletion of high energy compounds.
  • Use of alternate energy substrate - the neonatal brain has the capacity to use lactate and ketone bodies for energy production.
  • The relative resistance of the fetal and neonatal myocardium to hypoxia ischemia.
  • Potential protective role of fetal hemoglobin.
foundation fact1
Foundation Fact
  • The ability to identify infants at highest risk for progressing to hypoxic-ischemic encephalopathy is critical for two reasons

a)The therapeutic window i.e. that time whereby intervention strategies may be effective in preventing the processes of ongoing injury in the newborn brain is short and considered to be less than six hours

b) Novel therapeutic strategies to prevent ongoing injury have the potential for significant side effects

early identification of high risk infants
Early Identification of High Risk Infants

1) Evidence of an Acute Perinatal Insult

Indicated by a combination of markers*

1) Sentinel event

2) Delivery room resuscitation

3) 5 Minute Apgar score  5

4) Cord arterial pH  7.00

+

2) Postnatal evidence of encephalopathy

1) Clinical

2) EEG

* Sensitivity (80%), Specificity 98%, Positive Predictive value (50%)

Perlman & Risser Pediatrics 97,1996

slide35

Clinical: Assessment of Encephalopathy

Staging of Encephalopathy

Stage 1 - Mild

Stage 2 - Moderate

Stage3 - Severe

Neurologic Evaluation

Level of Consciousness

Neuromuscular control

Reflexes

Autonomic function

Evidence of Seizures

Sarnat Arch of Neurol. 33;696,1976

long term outcome of term infants with perinatal hypoxic ischemic encephalopathy
DeathDisability

Mild 0 0

Moderate 6% 30%

Severe 60% 100%

Long term outcome of term infants with Perinatal Hypoxic-Ischemic Encephalopathy
a eeg assessment of cerebral function

a-EEG: Assessment of Cerebral Function

A Cerebral Function Monitor via a single channel EEG (a-EEG), records activity from two biparietal electrodes. The signal is smoothed and the amplitude integrated.

Three distinct patterns of electrical activity are noted i.e. normal, moderate and severe suppression.

Early evidence of moderate and/or severe suppression identifies abnormal neurologic outcome with a sensitivity of 100%, positive predictive value of 85% and negative predictive value of 100%.

Naqeeb, et al. Pediatrics 1999:103:1263

slide38

Representative aEEG tracings

Normal

Moderate

Suppression

Severe

Suppression

slide39
Abnormalities in both the Clinical and a-EEG evaluation enhances the early detection of infants who progress to irreversible brain injury.

Study Criteria*

1) 50 infants with an acute perinatal insult

2) Clinical examination within 6 hours-

Abnormal = Sarnat stage 2 or 3 encephalopathy

3) Simultaneous a-EEG assessment

Abnormal = Moderate or severe suppression

4) Persistent encephalopathy > 5 days was the

outcome of interest- this developed in 14/50 infants

* Shalak et al Pediatrics in press

slide40

Prediction of Persistent Encephalopathy (n=14) based oneither an abnormal clinical or a-EEG evaluation, or a combination of abnormalities in both

Test N S SP PPV NPV

Abnormal Exam 19 78% 78% 58% 90%

Abnormal EEG 1589% 73% 91% 91%

Both Abnormal 1378% 94% 85% 92%

N=number potentially enrolled in a study, S= sensitivity SP=specificity

PPV=positive predictive value, NPV=negative predictive value

management of the infant at risk for hypoxic ischemic cerebral injury
Management of the Infant at Risk for Hypoxic - Ischemic Cerebral Injury
  • Delivery Room
  • Beyond the Delivery Room
slide42

HYPOXIA-ISCHEMIA

ANAEROBIC GLYCOGLYSIS

ATP

ADENOSINE

GLUTAMATE

LACTATE

NMDA RECEPTOR

HYPOXANTHINE

INTRACELLULAR Ca+

XANTHINE

OXIDASE

ACTIVATES

NOS

ACTIVATES LIPASES

XANTHINE

FREE FATTY ACIDS

O2

NITRIC OXIDE

O2

FREE RADICALS FREE RADICALS FREE RADICALS

room air ra versus 100 o2
Room Air (RA)versus 100% O2
  • There is considerable debate whether to use RA versus 100% during DR resuscitation. This is highly relevant given the importance of free radicals in the genesis of ongoing injury.
  • Studies indicate that RA versus 100% O2 during DR resuscitation in term infants appears to be comparable with regard to short term outcome measures i.e. encephalopathy and /or death within 7 days

Ramji et al Pediatr Res 1993;34:809, Saugstad etal Pedaitrics 1998;102;e1

room air ra versus 100 o2 new data

)

  • Infants n=40 and >36 weeks with “Asphyxia” - umbilical PaO2 <
  • 70 mmHg PaCO2 > 60 mmHg pH < 7.15 and clinical - hypotonia, apnea,
  • bradycardia (<80BPM) were randomly resuscitated with RA or 100% O2.
  • RA vs O2 group needed
  • a)  time to first cry (1.2  0.6 vs 1.7  .05 min)
  • b)  time to regular respiratory pattern (4.6  0.7 vs 7.5  1.8 m)
  • c)  reduced-to-oxidized- glutathione ratio
Room Air (RA) versus 100% O2- new data

Vento et al Resuscitation with room air instead of 100% oxygen prevents oxidative

stress in moderately asphyxiated term neonates. Pediatrics 107;642-647:2001

management beyond the delivery room
Management Beyond the Delivery Room
  • General Measures
  • Neuroprotective Strategies
management beyond the delivery room general measures
Management Beyond the Delivery Room-General Measures
  • Ventilation
  • Fluid Status
  • Oliguria
  • Hypotension
  • Glucose status
  • Seizures
  • Cerebral edema
role of glucose
Role of Glucose
  • Both hyper and hypoglycemia may be seen in the post resuscitative phase.
  • Both may exacerbate neuronal injury
  • Hyperglycemia may contribute to  levels of lactate and thus to continuing acidosis
  • Hypoglycemia may contribute to injury particularly in parieto-occipito cortex
  • The goal should be to maintain glucose levels in the normal range
characteristics of infants with a blood sugar 40mg dl versus infants with a blood sugar 40mg dl
Characteristics of Infants with a Blood Sugar < 40mg/dl versus Infants with a Blood Sugar > 40mg/dl

Salhab et al Pediatrics 114 361.2004

management beyond the delivery room general measures1
Management Beyond the Delivery Room-General Measures
  • Ventilation
  • Fluid Status
  • Oliguria
  • Hypotension
  • Glucose status
  • Seizures
  • Cerebral edema
prophylactic phenobarbital
Prophylactic Phenobarbital
  • Thiopental (30mg/kg) initiated within two hours and infused for 24 hours did not alter the frequency of seizures or short term neurodevelopmental outcome. Systemic hypotension was a complication.
  • Phenobarbital (40mg/kg) administered between 1-6hours to asphyxiated infants, did not reduce neonatal seizures , but reduced neurodevelopmental sequelae i.e. 18% vs73% for controls at 3 years

Goldberg et al J Pediatr.1986, Hall et al J Pediatr 1998:132;345

management beyond the delivery room1
Management Beyond the Delivery Room
  • General Measures
  • Neuroprotective Strategies
neuroprotective strategies clinical issues
Neuroprotective strategies - Clinical issues

1) WHO TO TREAT - INFANT AT HIGHEST RISK.

2) WHEN TO TREAT - EARLY - THERAPEUTIC

WINDOW IS SHORT

3) HOW LONG TO TREAT - UNCLEAR.

4) WHAT TO TREAT WITH.

slide56

POTENTIAL STRATEGIES FOR PREVENTING REPERFUSION INJURY

HYPOXIA-ISCHEMIA

ANAEROBIC GLYCOGLYSIS

MILD HYPOTHERMIA

ATP

GLUTAMATE

ADENOSINE

NMDA RECEPTOR BLOCKER

MAGNESIUM SULFATE

DEXTROMETHORPHAN

KETAMINE

NMDA RECEPTOR

HYPOXANTHINE

Ca++

XANTHINE OXIDASE INHIBITORS

NOS

INHIBITORS

ALLOPURINOL

LIPASES

XANTHINE

NITRIC OXIDE

SYNTHASE

inhibitors

ARACHIDONIC

ACID

FREE RADICAL SCAVENGERS

SUPEROXIDE DISMUTASE

LAZEROIDS

FREE RADICALS

EICOSANOIDS

evidence of oxygen free radical injury
Evidence of Oxygen Free Radical Injury

1) Immature 7 day rats subjected to Hypoxic

Ischemic injury

2) The administration of Allopurinol or Saline 30

minutes prior to the insult resulted in treated

animals exhibiting less severe cerebral edema

at 42 hours when compared to controls

3) Chronic neuropathologic alterations were less

severe in the treated compared to control animals

Palmar et al Pediatr Res 1990

magnesium neuroprotection
Magnesium Neuroprotection

Adult Human Studies

1) Prevention of seizures with pre-eclampsia

2) Treatment of headache

3) Prevention of traumatic hearing loss

Animal studies

Conflicting data is noted- some studies indicate

neuroprotection, whereas others do not. Factors

such as timing of administration as well as dosing

appear to be important.

slide60

POTENTIAL STRATEGIES FOR PREVENTING REPERFUSION INJURY

HYPOXIA-ISCHEMIA

ANAEROBIC GLYCOGLYSIS

MILD HYPOTHERMIA

ATP

GLUTAMATE

ADENOSINE

NMDA RECEPTOR BLOCKER

MAGNESIUM SULFATE

DEXTROMETHORPHAN

KETAMINE

NMDA RECEPTOR

HYPOXANTHINE

Ca++

XANTHINE OXIDASE INHIBITORS

NOS

INHIBITORS

ALLOPURINOL

LIPASES

XANTHINE

NITRIC OXIDE

SYNTHASE

inhibitors

ARACHIDONIC

ACID

FREE RADICAL SCAVENGERS

SUPEROXIDE DISMUTASE

LAZEROIDS

FREE RADICALS

EICOSANOIDS

modest hypothermia as an intervention strategy
MODEST HYPOTHERMIA AS AN INTERVENTION STRATEGY
  • RECENT EVIDENCE INDICATES THAT THE MECHANISMS
  • MEDIATING NEURONAL DEATH FOLLOWING ISCHEMIA
  • ARE TEMPERTURE DEPENDENT.
  • MILD TO MODEST DECREASES IN BRAIN TEMPERATURE
  • MAY GREATLY INFLUENCE THE RESISTANCE OF THE
  • BRAIN TO BRIEF PERIODS OF ISCHEMIA.
potential mechanisms of action of hypothermia
Potential Mechanisms of Action of Hypothermia

Reduces cerebral metabolism

Preserves ATP levels

Decreases energy utilization

Suppresses Excitotoxic AA accumulation

Reduces NO synthase activity

Suppresses free radical activity

Inhibits apoptosis

Prolongs therapeutic window?

treatment of comatose survivors of out of hospital cardiac arrest with induced hypothermia
Treatment of Comatose Survivors of out-of-Hospital Cardiac Arrest with Induced Hypothermia

Outcome Hypothermia Normothermia

(n=43) (n=34)

Normal 15 7*

Moderate Disability 6 2

Severe Disability 0 2

Death 22 23

* P=.04 Unadjusted odds ratio for good outcome 2.65( CI,1.02 to 6.88)

Bernard et al NEJM 2002:346:557-563

mild therapeutic hypothermia to improve neurologic outcome after cardiac arrest
Mild Therapeutic Hypothermia to Improve Neurologic Outcome after Cardiac Arrest

Outcome Hypothermia Normothermia RR (95% CI) P value

Good Outcome 75/136(55%) 54/137(39%) 1.40 (1.08-1.81) 0.009

Death 56/137(41%) 76/138(55%) 0.74 (0.58-0.95) 0.02

The risk ratio(RR) was calculated as the rate of a favorable neurologic outcome

or the rate of death in the hypothermia group divided by the rate in the

normothermia group. One patient in each group was lost to followup

NEJM 2002;346:549

potential adverse effects of hypothermia in neonates
Potential Adverse Effects of Hypothermia in Neonates

Hypertension

Cardiac arrhythmia

Persistent acidosis

Increased oxygen consumption

Increased blood viscosity

Reduction in platelet count

Pulmonary hemorrhage

Sepsis

Necrotizing enterocolitis

slide67

How to Cool Babies?

- Selective

- Total Body

slide68

Selective Cooling

Systemic Cooling

Laptook et al Pediatrics 108:1301;2001

selective head cooling in term infants with intrapartum asphyxia early outcome pilot study
Selective Head Cooling in Term Infants with Intrapartum Asphyxia: Early Outcome: Pilot study

Degree of Cooling

Outcome Measure Control Minimal Mild

(n=10) (n=6) (n=6)

CT Scan

Abnormal 5 3 2

normal 2 2 4

EEG

Abnormal 2 3 0

normal 4 2 6

Dead 2 2 0

Neurological Deficits 3 2 0

Normal (6-12 months) 5 2 0

Mild temperature= 35.5-35.9 Gunn et al Pediatrics 1998

total body hypothermia for neonatal encephalopathy pilot study
Total Body Hypothermia for Neonatal Encephalopathy- Pilot study

Study Population

Term infants (n=16) with Birth Asphyxia

Cord arterial pH = 6.74 (median)

Abnormal a-EEG (n=10) Normal a-EEG (n=6)

Total body cooling to Managed as per routine

33.2C rectally for 48 hrs

Neonatal Seizures Normal Neonatal Course

Severe encephalopathy

Follow up(12-18m)

6 3 1 Normal Outcome

Minor Died CP

Abn.

Azzopardi Peds 2000;106:684

modest hypothermia as a neuroprotective strategy
Modest Hypothermia as a Neuroprotective Strategy
  • Two multicenter randomized studies evaluating hypothermia as a neuroprotective strategy have been conducted
  • The first utilizing selective hypothermia has been completed *.
  • No difference between hypothermia and controls for all patients were observed.
  • For infant with moderate encephalopathy (aEEG determined) more cooled versus control infants i.e. 52% versus 34% (p=0.02) had a favorable outcome. In addition the cooled versus control infants were less likely to be severely affected i.e. 11% versus 28% (p=0.03) respectively

* Gluckman et al Pediatr Res 2004

neuroprotective strategies

Neuroprotective Strategies

Hypothermia*

Oxygen Free Radical Inhibitors/Scavengers*

Prevention of Nitric Oxide Formation

Excitatory Amino Acid Antagonists

Growth Factors

*Strategies currently being evaluated in clinical trials.

future strategies
Future Strategies

Hypothermia expand the window of

opportunity

Adjunct therapies Growth factors

Free radical scavengers

NOS inhibitors

Supportive therapy Phenobarbital

conclusions1
Conclusions

1 Recent advances in the understanding of ongoing

injury following hypoxia-ischemia has facilitated

the implementation of neuroprotective strategies

which may reduce long-term neurologic morbidity

2. Future strategies should include optomizing both

supportive as well considering combination

therapy for infants at highest risk for severe brain

injury following intrapartum hypoxia-ischemia.