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Hypoxia - Ischemic

Encephalopathy

Ji ling
Background
 HIE is an acquired syndrome
characterized by clinical and laboratory
evidence of acute brain injury due to
asphyxia (ie, hypoxia, acidosis).
Background

 In spite of major advances in monitoring


technology and knowledge of fetal and
neonatal pathologies, perinatal asphyxia
or, more appropriately, hypoxic-ischemic
encephalopathy (HIE), remains a serious
condition, causing significant mortality
and long-term morbidity.
Pathophysiology
 Brain hypoxia and ischemia from
systemic hypoxemia and reduced
cerebral blood flow (CBF) are the
primary triggering events for HIE.
 Cerebral autoregulation of CBF
maintains brain perfusion (for awhile) in
spite of an initial drop in the mean BP.
Pathophysiology
 With prolonged asphyxia, the early compensatory
adjustments fail; CBF may become "pressure-
passive," at which time brain perfusion is dependent
on systemic BP. As BP falls, CBF falls below critical
levels and brain hypoxia occurs. This results in
intracellular energy failure. During the early phases
of brain injury, brain temperature drops and local
release of the neurotransmitter GABA increases;
these changes reduce cerebral oxygen demand,
transiently minimizing the impact of asphyxia.
Pathophysiology
 Reperfusion injury is a second determinant of
the extent of brain damage.
 By 6-24 hours after the initial injury, a new
phase of neuronal destruction sets in,
characterized by apoptosis (ie, programmed
cell death). Also known as "delayed injury," this
phase may continue for days to weeks.
Pathophysiology
 The severity of brain injury in this phase
correlates well with the severity of long-
term adverse neurodevelopmental
outcome in infants. Modern treatment
interventions are geared to reducing the
neuronal destruction that occurs during
this phase of HIE.
Pathophysiology
 A large cascade of biochemical events
follow HIE injury.
 Both hypoxia and ischemia increase the
release of excitatory amino acids (EAAs
[glutamate and aspartate]) in the cerebral
cortex and basal ganglia. EAAs begin
causing neuronal death immediately .
Pathophysiology
 the destruction of ion pumps is the lipid
peroxidation of cell membranes, in which
enzyme systems, such as the Na+/K+-ATPase,
reside. This leads to influx into the cell water,
cell swelling, and death.
 EAAs also increase the local release of nitric
oxide (NO), which may exacerbate neuronal
damage, although its mechanisms are unclear.
Mortality/Morbidity
 In severe HIE, the mortality rate is as high
as 50%. Half of the deaths occur in the first
month of life. Some infants with severe
neurologic disabilities die in infancy from
aspiration pneumonia and other infections.
 Among infants who survive severe HIE, the
most frequent sequelae are mental
retardation, epilepsy, and cerebral palsy
Mortality/Morbidity
 The incidence of long-term complications
depends on the severity of HIE.
 Up to 80% of infants surviving severe HIE
are known to develop serious
complications, 10-20% develop
moderately serious disabilities, and up to
10% are normal.
Mortality/Morbidity
 Among the infants who survive
moderately severe HIE, about 30-50%
have serious long-term complications,
and 10-20% have minor complications.
 Infants with mild HIE tend to be free
from serious CNS complications.
Mortality/Morbidity
 Even in the absence of obvious neurologic deficits
in the newborn period, there may be long-term
functional impairments. Of school-aged children
with a history of moderately severe HIE, 15-20%
had significant learning difficulties, even in the
absence of obvious signs of brain injury. Because
of this, all children who have moderately severe or
severe HIE as infants should be monitored well
into their school-age years.
CLINICAL
 History:
a) Profound metabolic or mixed acidemia
(pH <7.00) in an umbilical artery blood
sample, if obtained
b) Persistence of an Apgar score of 0-3
for longer than 5 minutes
c) Neonatal neurologic sequelae (eg,
seizures, coma, hypotonia)for more
than 24h
Apgar score
It is a useful quantitative
assessment of the infant’s
condition and is commonly
determined at 1 and 5 minutes
after birth.
Apgar score evaluation of the newborn

criteria score
0 1 2

Heart rate absent <100 beats/min >100 beats/min

Respiratory Absent/weak Slow,irregular/gasping Good,regular


effort
Muscle tone Limp,flaccid Some flexion Active
movements
Reflex none weak Cries,coughs or
response to sneezes
stimulation
Colour of the Blue or pale Extremities blue pink
body
CLINICAL
 History:
d) Multiple organ involvement (eg, of the
kidney, lungs, liver, heart, intestines)
e) On rare occasions, difficulties with
delivery, particularly problems with
delivering the "after-coming" head in
breech presentation, suggest an alternate
diagnosis of hemorrhage in the posterior
cerebral fossa, which is a rare condition.
CLINICAL
 Physical: Clinical manifestations and course vary
depending on HIE severity.
 Mild HIE
1) Muscle tone may be increased slightly and deep
tendon reflexes may be brisk during the first few days.
2) Transient behavioral abnormalities, such as poor
feeding, irritability, or excessive crying or sleepiness,
may be observed.
3) By 3-4 days of life, the CNS examination findings
become normal.
CLINICAL
 Moderately severe HIE
1) The infant is lethargic, with significant hypotonia and diminished
deep tendon reflexes.
2) The grasping, Moro, and sucking reflexes may be sluggish or
absent.
3) The infant may experience occasional periods of apnea.
4) Seizures may occur within the first 24 hours of life.
5) Full recovery within 1-2 weeks is possible and is associated with a
better long-term outcome.
6) An initial period of well-being may be followed by sudden
deterioration, suggesting reperfusion injury; during this period,
seizure intensity might increase.
CLINICAL
 Severe HIE
1) Stupor or coma is typical. The infant may not
respond to any physical stimulus.
2) Breathing may be irregular, and the infant often
requires ventilatory support.
3) Generalized hypotonia and depressed deep
tendon reflexes are common.
4) Neonatal reflexes (eg, sucking, swallowing,
grasping, Moro) are absent.
CLINICAL
5)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.
6)Pupils may be dilated, fixed, or poorly
reactive to light.
CLINICAL
7)Seizures occur early and often and may be initially
resistant to conventional treatments. The seizures
are usually generalized, and their frequency may
increase during the 2-3 days after onset,
correlating with the phase of reperfusion injury. As
the injury progresses, seizures subside and the
EEG becomes isoelectric or shows a burst
suppression pattern. At that time, wakefulness
may deteriorate further, and the fontanelle may
bulge, suggesting increasing cerebral edema.
CLINICAL
8)Irregularities
of heart rate and BP are
common during the period of
reperfusion injury, as is death from
cardiorespiratory failure.
CLINICAL
 Involvement of multiple organs besides the
brain is a hallmark of HIE.
1) Severely depressed respiratory and cardiac
functions and signs of brainstem compression
suggest a life-threatening rupture of the vein of
Galen (ie, great cerebral vein) with a hematoma in
the posterior cranial fossa.
2) Reduced myocardial contractility, severe
hypotension, passive cardiac dilatation, and tricuspid
regurgitation are noted frequently in severe HIE.
CLINICAL
3) Patients may have severe pulmonary hypertension
requiring assisted ventilation.
4) Renal failure presents as oliguria and, during
recovery, as high-output tubular failure, leading to
significant water and electrolyte imbalances.
5) Intestinal injuries may not be apparent in the first
few days of life. Poor peristalsis and delayed
gastric emptying are common; necrotizing
enterocolitis occurs rarely.
•Table 1. Sarnat and Sarnat's 3 Clinical Stages of
Hypoxic Ischemic Brain Injury
State 1 Stage 2 Stage 3

Level of Lethargic or Stuporous or


Hyperalert
Consciousness obtunded coma

Neuromuscular Control

Muscle tone Normal Mild hypotonia Flaccid

Mild distal Strong distal Intermittent


Posture
flexion flexion decerebration

Decreased or
Stretch reflexes Overactive Overactive
absent

Segmental
Present Present Absent
myoclonus
State 1 Stage 2 Stage 3
Complex Reflexes

Suck Weak Weak or absent Absent

Moro Absent
Strong; Weak; incomplete;
Oculovestib Weak or
Normal Overactive
ular absent
Tonic neck Slight Strong Absent

Generalized
Autonomic Generalized Both systems
parasympatheti
Function sympathetic depressed
c
Variable; often
Pupils Mydriasis Miosis unequal; poor light
reflex

Heart Rate Tachycardia Bradycardia Variable

Bronchial and
Salivary Sparse Profuse Variable
Secretions
State 1 Stage 2 Stage 3

Gastrointestin Normal or Increased;


Variable
al Motility decreased diarrhea

Uncommon
Common; focal
Seizures None (excluding
or multifocal
decerebration)

Electroenceph Normal Early: low-voltage Early: periodic pattern


alogram (awake continuous delta and with Isopotential
Findings ) theta phases
Later: periodic Later: totally
pattern (awake) isopotential
Seizures: focal 1-to
1-Hz spike-and-wave

Duration <24 h 2-14 Hours to weeks


DIFFERENTIALS
Other Problems to be Considered:
 Brain tumors
Developmental defects
Infections
Inherited metabolic disorders such as
disorders of urea cyclase deficiency
workup
 Lab Studies:
No specific test excludes or
confirms a diagnosis of HIE.
Serum electrolytes,
Renal function studies
 Imaging Studies:
Cranial ultrasound
CT scan of the head
MRI
 Other Tests:
EEG
Treatment
 Medical Care:
 Treatment of seizures is an essential
component of management. Seizures
should be treated with phenobarbital or
lorazepam;
Treatment
 Drug Category: Anticonvulsants -- Used
to control seizures
Phenobarbital
20 mg/kg IV over 10-15 min as loading
dose; additional 5-10 mg/kg IV as
loading dose; followed by 3-5 mg/kg/d
Treatment
Cardiovascular (inotropic) agents --

Increase BP and combat shock.
Dopamine (Intropin)
2-20 mcg/kg/min IV continuous infusion;
begin at lower doses, increase on basis
of systemic BP appropriate for age and
gestational age
Treatment
 No specific therapy for HIE exists; after
seizure control, supportive care remains
the cornerstone of management. The
elements of supportive care are as
follows:
Treatment
• Maintain adequate ventilation, perfusion, and
metabolic status; most infants with HIE need
ventilatory support during the first week.
• Prevent hypoxia, hypercapnia, and
hypocapnia; the latter is due to inadvertent
hyperventilation, which may lead to severe
hypoperfusion of the brain.
Treatment
• Maintain the blood gases and acid-base status in the
physiological ranges including partial pressure of
arterial oxygen (PaO2), 80-100 mm Hg; partial
pressure of arterial carbon dioxide (PaCO2), 35-40
mm Hg; and pH, 7.35-7.45.
• Maintain the mean BP above 35 mm Hg (for term
infants). Dopamine or dobutamine can be used to
maintain adequate cardiac output.
• Fluid, electrolyte, and nutritional status should be
monitored and corrected and adequate calories and
proteins provided.
Treatment
o Avoid hypoglycemia or hyperglycemia, as both are
known to cause brain injury.
o In the first 2 days of life, restrict intravenous fluids to
two thirds of the daily requirement for gestational age
and nursing environment in light of the high frequency
of acute tubular necrosis and IADH.
o Individualize fluid and electrolyte therapy on the basis
of clinical course, changes in weight, urine output,
and results of serum electrolyte and renal function
studies.
Prevention
 Most of the treatments discussed here
are experimental. With the exception of
hypothermia, which is still being
examined in clinical trials, none of the
therapies cited below has been
consistently shown to have efficacy in
human infants.
Prevention
• Allopurinol: Slight improvements in survival
and CBF were noted in a small group of
infants tested with this free-radical scavenger
in one clinical trial.
• High-dose phenobarbital: In another study, 40
mg/kg phenobarbital was given over 1 hour to
infants with severe HIE.
Prevention
• EAA antagonists: MK-801, an EAA
antagonist, has shown promising results in
experimental animals . This drug has serious
cardiovascular adverse effects.
Prevention
 Hypothermia: Currently being intensely tested
as a neuroprotective therapy, hypothermia's
mechanism of protection is not completely
understood. Explanations include (1) reduced
metabolic rate and energy depletion; (2)
decreased excitatory transmitter release; (3)
reduced alterations in ion flux; and (4)
reduced vascular permeability, edema, and
disruptions of blood-brain barrier functions.
The current state-of-the-art on hypothermia is
summarized by the following:
Cooling

Insult
Latent Secdonary
EEG low Seizure
CBF↓ Cytotoxic edema
Apoptotic cascade Excitoxin

Reperfusion

Min,~30 H, 6~15 D, 3
Prevention
o Brain cooling to about 3-4°C below the
baseline temperature (ie, to 33-34°C) may be
neuroprotective. The optimal level of
hypothermia for maximal neuroprotection is
not known. Extreme hypothermia may cause
significant systemic side effects.
o Up to 48-72 hours of cooling may be needed
to prevent secondary neuronal loss. The
greater the severity of the initial injury, the
longer the duration of hypothermia needed for
optimal neuroprotection.
Prevention
o Cooling must be begun early, within 1 hour of injury, if
possible; however, favorable outcome may be possible if
cooling is begun up to 6 hours after injury.
o A special device that selectively cools the head is now
being tested in clinical studies; it is not available in the
market. Some investigators believe that total body
cooling (as done for open-heart surgery) may be superior
to selective head cooling. The relative merits and
limitations of different methods of brain cooling have not
been studied.
Prevention
o Hypothermia may cause significant side effects,
including coagulation defects, leukocyte malfunctions,
pulmonary hypertension, and worsening of metabolic
acidosis. Until more is learned, hypothermia remains
an experimental modality
Prognosis
 Accurate prediction of the severity of
long-term complications is difficult,
although the following pointers may be
used:
Prognosis
• Lack of spontaneous respiratory effort within
20-30 minutes of birth is associated with
almost uniform mortality.
• 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.
Prognosis
• Abnormal clinical neurological findings persisting beyond
the first 7-10 days of life usually indicate poor prognosis.
Among these, abnormalities of muscle tone and posture
(hypotonia, rigidity, weakness) should be carefully
noted.
• 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.

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