PERINATAL

HYPOXIA-ISCHEMIA (H/I)
MIHAI CRAIU MD PhD

TERMINOLOGY
PERINATAL HYPOXIA-ISCHEMIA acute
process
HYPOXIC-ISCHEMIC ENCEPAHALOPATHY
long term sequelae of P H/I

DEFINITION
Perinatal hypoxia-ischemia (H/I) refers
to exposure to low oxygen (hypoxia) and
decreased blood flow (ischemia) prior
to, during, or soon after birth.
Perinatal cerebral hypoxia-ischemia is a
frequent cause of the chronic
handicapping conditions
cerebral palsy,
mental retardation
epilepsy.

CONSEQUENCES OF P H/I 1
Estimates* suggest that between 2and
4/1000 full-term newborn infants suffer
asphyxia at or shortly before birth.
Approximately 15% to 20% of such
asphyxiated infants who exhibit hypoxicischemic encephalopathy actually die during
the newborn period.
Of the survivors, 25% will exhibit permanent
neuropsychologic deficits.
*Vanucci RC, Perlman JM - Interventions for Perinatal HypoxicIschemic Encephalopathy. PEDIATRICS 1997;100(6):1004-1114

CONSEQUENCES OF P H/I 2
Recent estimates* are more
optimistic: 1-2/1000 newborn infants
suffer asphyxia at or shortly before
birth.
*Stokowski LA - Modest Hypothermia for Term Infants
With Hypoxic-Ischemic Encephalopathy.
http:\\cme.medscape.com/viewarticle/519765.

LONG TERM PROGNOSIS 1

The incidence of long-term complications
depends on the SEVERITY of hypoxicischemic encephalopathy.
70-80% of infants who survive severe
hypoxic-ischemic encephalopathy develop
serious complications, 10-20% develop
moderately serious disabilities, and ~ 10%
have normal developmental aspects.
*Zanelli AS, Stanley DP. Hypoxic-Ischemic Encephalopathy.
www.eMedicine.com Updated: Dec 15, 2008

LONG TERM PROGNOSIS 2

Among those who survive moderately
severe hypoxic-ischemic
encephalopathy, 30-50% may have
serious long-term complications, and 1020% have minor neurological sequelae.
Infants with mild hypoxic-ischemic
encephalopathy tend to be free from
serious CNS complications.
*Zanelli AS, Stanley DP. Hypoxic-Ischemic
Encephalopathy. www.eMedicine.com Updated: Dec
15, 2008

HISTORY OF P H/I
Therapeutic interventions for HIE in
newborn infants consisted of drugs that
reduced the severity of cerebral edema.
Were used
osmotic diuretics
mannitol,
furosemide

corticosteroids
barbiturates.

HISTORY OF P H/I
Presently none of these agents has been
proven useful to ameliorate PHI-induced
brain damage in the clinical setting.
All these drugs and other treatments to
treat brain swelling are not any longer in use.

AAP* & ACOG** GUIDELINES

FOR HIE DIAGNOSIS
All of the following must be present for the designation of perinatal
asphyxia severe enough to result in acute neurological injury:
Profound metabolic or mixed acidemia (pH <7) in an umbilical artery
blood sample,
Persistence of an Apgar score of 0-3 for longer than 5 minutes
Neonatal neurologic sequelae (eg, seizures, coma, hypotonia)
Multiple organ involvement (eg, kidney, lungs, liver, heart, intestines)
* American Academy of Pediatrics.Relation between perinatal factors and neurological
outcome.In: Guidelines for Perinatal Care.3rd ed.Elk Grove Village, Ill:American
Academy of Pediatrics;1992:221-234.
**Committee on fetus and newborn, American Academy of Pediatrics and Committee on
obstetric practice, American College of Obstetrics and Gynecology.Use and abuse of the
APGAR score.Pediatr.1996;98:141-142.

PATHOPHISIOLOGY OF P H/I 1
At cellular level, when cerebral perfusion is
too low to provide adequate cerebral
oxygenation, a cascade of biochemical events
is initiated:

energy failure,
acidosis,
free-radical formation,
Ca++ accumulation,
lipid peroxidation,
neurotoxicity from glutamate and nitric oxide.

MECHANISMS OF P H/I 2
Hypoxic-ischemic brain
damage is an evolving
process, which begins
during the insult and
extends into the
recovery period after
resuscitation
(reperfusion interval).

MECHANISMS OF P H/I 3
Brain hypoxia and ischemia due
to systemic hypoxemia and/or
reduced cerebral blood flow
(CBF) are the primary
physiological processes that
lead to HIE.
The initial compensatory
adjustment is an increase in the
CBF due to hypoxia and
hypercapnia.
This is accompanied by a
redistribution of cardiac output:
the brain receives an increased
proportion of the cardiac
output.

MECHANISMS OF P H/I 4
Following the initial phase
of energy failure from the
asphyxial injury, cerebral
metabolism may recover,
only to deteriorate in the
secondary phase
(reperfusion)
This new phase, starting at
~ 6-24 hours after the
initial injury, is
characterized by cerebral
edema and apoptosis.

PATHOPHISIOLOGY OF P H/I
It is during this interval after
resuscitation from hypoxiaischemia
that an intervention to reduce the
severity of ongoing brain damage might
be efficacious.

ADAPTATIVE MECHANISMS
The absence of complications in most
acidotic newborn children reflects the
adaptive capacity of the fetus to
withstand an asphyxial insult.

ADAPTATIVE MECHANISMS
Mechanisms contributing to neuronal
preservation:
redistribution of cardiac output,
increased cerebral and myocardial blood flow
decreased flow to less vital organs,

a slower depletion of high-energy compounds

during hypoxiaischemia,
use of alternative substrates (e.g., lactate
and ketone bodies) as sources of energy,

CAUSES OF HIE

PREDICTING * OF P H/I
Activin A concentrations were >0.08 g/L at first
urination in 10 of 12 patients with moderate or
severe HIE but in none of 18 patients with no or
mild HIE.
Conclusions: Activin A measurements in urine
soon after birth may be a promising tool to
identify which asphyxiated infants are at risk of
neurological sequelae.
*Florio P, Luisi S et al - High Urinary Concentrations of Activin A in

Asphyxiated Full-Term Newborns with Moderate or Severe Hypoxic

Ischemic Encephalopathy. Clinical Chemistry. 2007;53:520-522.

PREDICTING * OF P H/I
Measurement of L:C (urinary lactate:
creatinine ratio ) soon after birth may
help identify infants at high risk for
hypoxicischemic encephalopathy *.
Huang CC, Wang ST et al - Measurement of the Urinary
Lactate:Creatinine Ratio for the Early Identification of
Newborn Infants at Risk for HypoxicIschemic Encephalopathy.
N Engl J Med 1999;341:328-335.

PREDICTING OF P H/I
IN RESEARCH SETTINGS

Samples of CSF are rarely obtained from

infants with no clinical signs of HIE and are
dangerous to obtain from infants with
evidence of increased intracranial pressure.
Measurements (in serum or CSF) that can be
used as markers of HIE are:

neuron-specific enolase,
lactate dehydrogenase,
hydroxybutyrate dehydrogenase,
glial fibrillary acidic protein,
brain-specific creatine-kinase,
glutamate,
interleukin-6.

CLINICAL ASPECTS 1
Mild hypoxic-ischemic encephalopathy
Muscle tone may be slightly increased and
deep tendon reflexes may be brisk during the
first few days.
Transient behavioral abnormalities, such as
poor feeding, irritability, excessive crying or
sleepiness, may be observed.
By 3-4 days of life, the CNS examination
findings become normal.

CLINICAL ASPECTS 21
Moderately severe hypoxic-ischemic
encephalopathy

The infant is lethargic, with significant

hypotonia and diminished deep tendon reflexes.
The grasping, Moro, and sucking reflexes may be
sluggish or absent.
The infant may experience occasional periods of
apnea.
Seizures may occur within the first 24 hours of
life.

CLINICAL ASPECTS 22
Moderately severe hypoxic-ischemic
encephalopathy
Full recovery within 1-2 weeks is possible and is
associated with a better long-term outcome.
An initial period of well-being or mild HIE may
be followed by sudden deterioration, suggesting
ongoing brain cell dysfunction, injury and death;
during this period, seizure intensity might
increase.

CLINICAL ASPECTS 31
Severe hypoxic-ischemic encephalopathy

Stupor or coma is typical.

Breathing may be irregular; often requires ventilatory
support.
Generalized hypotonia and depressed deep tendon
reflexes are common.
Neonatal reflexes (eg, sucking, swallowing, grasping,
Moro) are absent.
Disturbances of ocular motion, such as a skewed
deviation of the eyes, nystagmus, bobbing and loss of
"doll's eye" (ie, conjugate) movements may be revealed
by cranial nerve examination. .

CLINICAL ASPECTS 32
Severe hypoxic-ischemic encephalopathy
Pupils may be dilated, fixed or poorly reactive to
light.
Seizures occur early and often may be resistant
to conventional treatments.
Seizures are usually generalized.
Frequency may increase during the 24-48 hours
after onset, correlating with the phase of
reperfusion injury.

CLINICAL ASPECTS 33
Severe hypoxic-ischemic encephalopathy

As the injury progresses, seizures subside and

the EEG becomes isoelectric or shows a burst
suppression pattern.
At that time, wakefulness may deteriorate
further; the fontanelle may bulge, suggesting
increasing cerebral edema.
Irregularities of heart rate and blood pressure
are common during reperfusion injury,
Many of these children die.

MULTIPLE-ORGAN
DISFUNCTION IN HIE 1
Heart (43-78%): May present as
reduced myocardial contractility, severe
hypotension, passive cardiac dilatation
and tricuspid regurgitation.
Lungs (71-86%):Patients may have
severe pulmonary hypertension requiring
assisted ventilation
Renal (46-72%): Renal failure presents
as oliguria and, during recovery, as highoutput tubular failure.

MULTIPLE-ORGAN
DISFUNCTION IN HIE 2
Liver (80-85%): Elevated liver function test
results,hiperammonemia, coagulopathy can be
seen.
GI dysfunction(80%): Poor peristaltic movements
and delayed gastric emptying are common;
necrotizing enterocolitis is rare. Intestinal
injuries may not be apparent in the first few days
of life or until feeds are initiated.
Hematologic (32-54%):Disturbances include
increased nucleated RBCs, neutropenia or
neutrophilia, thrombocytopenia, and coagulopathy.

MULTIPLE-ORGAN
DISFUNCTION IN HIE 3
Severely depressed respiratory and
cardiac functions and signs of brainstem
compression suggest a life-threatening
rupture of the vein of Galen with a
hematoma in the posterior cranial fossa.

SARNATs STAGES OF HIE1

Sarnat HB, Sarnat MS.Neonatal encephalopathy following fetal distress: A clinical

and electroencphalographic study.Archives of Neur.1976;33:696-705.

SARNATs STAGES OF HIE2

Sarnat HB, Sarnat MS.Neonatal encephalopathy following fetal distress: A clinical

and electroencphalographic study.Archives of Neur.1976;33:696-705.

DIFFERENTIALS
Other inborn errors of metabolism :
nonketotic hyperglycinemia,
disorders of pyruvate metabolism,
urea cycle defects

Mitochondrial disorders
Neuromuscular disorders including neonatal
myopathies
Brain tumors
Developmental defects
Infections

HYPOXIC-ISCHEMIC BRAIN INJURY:

IMAGING FINDINGS FROM BIRTH TO
ADULTHOOD

Factors such as
brain maturity,
duration and
severity of insult,
and type and timing
of imaging studies all
influence findings in
HIE.

HYPOXIC-ISCHEMIC BRAIN INJURY:

IMAGING FINDINGS FROM BIRTH TO
ADULTHOOD
Severe hypoxia-ischemia in both preterm
and term neonates preferentially
damages the deep gray matter.
Less profound insults result in:
intraventricular hemorrhages and
periventricular white matter injury in
preterm neonates
parasagittal watershed territory infarcts in
term neonates.

HYPOXIC-ISCHEMIC BRAIN INJURY:

IMAGING FINDINGS FROM BIRTH TO
ADULTHOOD
In the postnatal period, severe insults
result in diffuse gray matter injury.
Profound hypoxia-ischemia in older
children and adults affects the deep
gray matter nuclei, cortices, hippocampi,
and cerebellum.

CRANIAL ULTRASOUND
NATIVE or DOPPLER

BRAIN DEATH IMAGING

BY FUNCTIONAL
SCINTIGRAPHIC SCANS
(NON-PERFUSED BRAIN)

THERAPEUTIC WINDOW
The exact duration of the so-called
therapeutic window is unknown, but is
considered to be only a few hours (2-6
hours) after birth.
Imaging techniques, such as cranial
ultrasound scans and magnetic
resonance imaging (MRI), are useful for
prognosis, but not until 24hours or
more after birth.

EEG 1
Postnatal evaluation after perinatal
asphyxia using EEG can reliably predict
neurodevelopmental outcome, as early as
3hours after birth *.
* Toet MC, Hellstrm-Westas L et al - Amplitude
integrated EEG 3and 6hours after birth in full term
neonates with hypoxic-ischaemic encephalopathy.
Arch Dis Child Fetal Neonatal Ed 1999;81:F19-F23

EEG 2
An EEG could be useful for selecting
those infants who might benefit from
early intervention after perinatal
asphyxia, and because of its high
negative predictive value (84%), avoid
unnecessary risks related to treatment
for those infants that do not need
intervention.

de VriesLS; Hellstrm-WestasL - Role of cerebral

function monitoring in the newborn.
Arch Dis Child Fetal Neonatal Ed. 2005; 90(3):F201-7

TREATMENT OPTIONS
LIFE SUPPORT MEASURES
Most infants with severe HIE need
respiratory support during the first week.
Maintain the blood gases and acid-base
status in the physiological ranges.

SEIZURE CONTROL
phenobarbital, lorazepam, phenytoin

HYPOTHERMIA

NEUROPROTECTION 1
In 2005, the National Institute
of Child Health and Human
Development (NICHD)
evaluated the status of
knowledge regarding the safety
and efficacy of hypothermia as
a neuroprotective therapy for
neonatal hypoxic-ischemic
encephalopathy (HIE)*.
*Higgins R, Raju T, Perlman J, et al.
Hypothermia and perinatal asphyxia: executive
summary of the NICHD Workshop. J Pediatr.
2006;148 :170 175

NEUROPROTECTION 2
Potential therapeutic strategies for
neuroprotection = administration of magnesium*.
Mg is blocking glutamate-controlled N-methyl-Daspartate (NMDA) receptors and the voltagedependent calcium channels, preventing the
influx of extracellular calcium into the neurons,
as well as its action as a membrane stabilizer.
Variable results.
* Leone RC, Barbosa NOE - Magnesium and Perinatal Asphyxia.
NeoReviews Vol.8 No.9 2007 e387

NEUROPROTECTION
RESEARCH
Animal models
Administration of hypothermia or xenon alone, 1 and 6h
after the hypoxic ischaemic insult, respectively, provided
no neuroprotection.
Asynchronous administration of xenon and hypothermia
at a 1h interval produced a significant reduction in
infarct volume [93 (7) vs 74 (8); P < 0.05]. Reduction in
infarct volume was also present when hypothermia and
xenon were asynchronously administered with an
intervening gap of 5h [97 (5) vs 83 (3); P < 0.05].
* Martin LJ, Ma D et al -Asynchronous administration of xenon and

hypothermia significantly reduces brain infarction in the neonatal

rat. British Journal of Anaesthesia 2007 98(2):236-240

PREDICTION OF SEVERITY
FOR LONG-TERM SEQUELAE 1
Following pointers may be used:
Lack of spontaneous respiratory effort
within 20-30 minutes of birth almost
always associated with death.
The presence of seizures is an ominous
sign. The risk of poor neurological
outcome is distinctly greater in such
infants, particularly if seizures occur
frequently and are difficult to control.

PREDICTION OF SEVERITY
FOR LONG-TERM SEQUELAE 2
Abnormal clinical neurological findings
persisting beyond the first 7-10 days of
life usually indicate poor prognosis.
Abnormalities of muscle tone and
posture (hypotonia, rigidity, weakness)
should be carefully noted.

PREDICTION OF SEVERITY
FOR LONG-TERM SEQUELAE 3
Persistent feeding difficulties, which
generally are due to abnormal tone of
the muscles of sucking and swallowing,
also suggest significant CNS damage.
Poor head growth during the postnatal
period and the first year of life is a
sensitive finding predicting higher
frequency of neurologic deficits.

PREDICTION OF SEVERITY
FOR LONG-TERM SEQUELAE 4
If CNS examination findings become
normal by 3-4 days of life is a good
prognostic sign .
An EEG done at about 7 days that has
normal background activity is a good
prognostic sign.