This document discusses hypoxic ischemic encephalopathy (HIE), focusing on recent advances. It provides data on the scope of the problem, defining key terms like HIE, perinatal asphyxia, and neonatal encephalopathy. It discusses the etiology and risk factors for HIE, as well as the pathophysiology involving disrupted cerebral blood flow, energy metabolism, excitotoxicity, oxidative stress, inflammation, and apoptosis. Indian data on HIE is presented based on Apgar scores and neurological manifestations.

1. Hypoxic Ischemic Encephalopathy
with a focus on recent advances
Moderator : Dr.B.P.Kalra
Presenter: Dr.Varun Mamgain

2. Scope Of The Problem
• occurs in up to 6 /1000 live term births
• a major cause of neurodevelopmental disability,
with one-quarter of survivors sustaining
permanent neurological deficits

3. Indian data
• In India, Apgar scores <7 at 1 minute (includes
moderate and severe asphyxia) were documented
in 9% of all intramural deliveries
• 2.5% babies continued to have Apgar scores <7 at
5 minutes of age.

4. • Manifestations of HIE seen in approx 1.5%

5. Definitions
Hypoxia or Anoxia: A partial (hypoxia) or complete
(anoxia) lack of oxygen
Hypoxemia - A partial (hypoxia) or complete (anoxia)
lack of oxygen in the brain or blood
Asphyxia: The state in which placental or pulmonary
gas exchange is compromised or ceases altogether
Ischemia: The reduction or cessation of blood flow to
an organ which compromises both oxygen and
substrate delivery to the tissue

6. • Perinatal Asphyxia refers to a condition during
the first and second stage of labor in which
impaired gas exchange leads to fetal hypoxemia
and hypercarbia.
• identified by fetal acidosis as measured in
umbilical arterial blood.
• the most widely accepted definition of fetal
acidosis is a pH<7.0, even with this degree of
acidosis, the likelihood of brain injury is low.

7. • Perinatal Asphxia is a combination of Hypoxia,
Hypercarbia, Metabolic acidosis
• According to American Academy of Pediatrics,
perinatal asphyxia is described as
• Cord umbilical PH < 7 with base deficit of <10
mEq/l
• Neonatal neurologic manifestation suggestive
of HIE
• Evidences of multi organ failure (CVS ,Renal etc)

8. WHO Definition
• a “failure to initiate and sustain breathing at
birth”
• WHO/NNF – Apgar 0-3 at 1 minute – severe
asphyxia,4-7 – moderate asphyxia
• In Community Settings NNF defines – asphyxia
as absence of cry at 1 minute, severe asphyxia
as absent or inadequate breathing at five
minutes

9. The National Neonatal Perinatal
Database (NNPD), 2000
• defined moderate asphyxia as slow gasping
breathing or an Apgar score of 4-6 at 1 minute of
age
• Severe asphyxia was defined as no breathing or
an Apgar score of 0-3 at 1 minute of age.

10. • Perinatal/neonatal depression is a clinical,
descriptive term that pertains to the condition of
the infant on physical examination in the immediate
postnatal period (i.e., in the first hour after birth).
• clinical features
– depressed mental status,
– muscle hypotonia,
– disturbances in spontaneous respiration and
cardiovascular function.
– Term makes no association with the prenatal or later
postnatal condition, physical exam, laboratory tests,
imaging studies, or electroencephalograms (EEGs).

11. After the first hour
• Neonatal encephalopathy is a clinical and not an
etiologic term that describes an abnormal
neurobehavioral state consisting of decreased
level of consciousness and usually other signs of
brain stem and/or motor dysfunction.
– does not imply a specific etiology, nor does it imply
irreversible neurologic injury as it may be caused by
such reversible conditions as maternal medications or
hypoglycemia.

12. • Hypoxic-ischemic encephalopathy (HIE) describes
encephalopathy as defined before, with objective data to
support a hypoxic-ischemic mechanism as the underlying
cause for the encephalopathy.
• Hypoxic-ischemic (HI) brain injury refers to
neuropathology attributable to hypoxia and/or ischemia
as evidenced by
– biochemical (such as serum creatine k inase brain bound [CK-
BB]),
– electrophysiologic (EEG),
– neuroimaging (head ultrasonography [HUS], magnetic resonance
imaging [MRI], computed tomog-raphy [CT]),
– pathologic (postmortem) abnormalities.

13. ETIOLOGY
• In term newborns, asphyxia can occur in the
antepartum or intrapartum period
• result of impaired gas exchange across the placenta
– inadequate provision of oxygen (O2)
– removal of carbon dioxide (CO2) and hydrogen (H2) from
the fetus.
• In the postpartum period, usually secondary to
pulmonary, cardiovascular, or neurologic
abnormalities

14. Factors that increase the risk of perinatal
asphyxia
• Impairment of maternal oxygenation
• Decreased blood flow from mother to
placenta
• Decreased blood flow from placenta to fetus
• Impaired gas exchange across the placenta or
at the fetal tissue level
• Increased fetal O2 requirement

15. Etiologies
• may be multiple and include the following:
• Preconceptual
– Advanced maternal age
– IDDM
– Thyroid disease
– Fertility Treatments
• Maternal factors:
– hypertension (acute or chronic),
– hypotension,
– infection (including chorioamnionitis),
– hypoxia from pulmonary or cardiac disorders, d iabetes,
maternal vascular disease, and in utero exposure to
cocaine

16. • Placental factors:
– abnormal placentation,
– abruption,
– infarction,
– fibrosis
• Uterine rupture
• Umbilical cord accidents:
– prolapse,
– entanglement,
– true knot,
– compression
• Abnormalities of umbilical vessels
• Instrumentation
• Stat C-Section

17. • Fetal factors:
– anemia,
– infection,
– cardiomyopathy,
– hydrops,
– severe cardiac/ circulatory insufficiency
• Neonatal factors:
– cyanotic congenital heart disease,
– persistent pulmonary hyper-tension of the newborn
(PPHN),
– cardiomyopathy,
– neonatal cardio-genic and/or septic shock

18. Pathophysiology
• Hypoxia-ischemia causes a number of physiologic
and biochemical alterations
• The adverse consequences of cerebral ischemia
include deprivation of energy substrates and
oxygen, and an inability to clear accumulated,
potentially toxic metabolites.

19. • Cerebral Blood Flow and Energy Metabolism
• Excitotoxicity
• Oxidative Stress
• Inflammation
• Apoptosis

20. Cerebral Blood Flow and Energy Metabolism
• Disruption of cerebrovascular autoregulation - important
factor in the pathophysiology of neonatal hypoxic-ischemic
brain injury.
• widely accepted that preterm infants have a “pressure-
passive” cerebral circulation; however,
• term infants may remain at risk for impairment of
cerebrovascular autoregulation and susceptibility to
cerebral ischemia with fluctuations in systemic blood
pressure.

22. • With brief asphyxia, there is
– a transient increase, followed by a decrease in heart
rate (HR)
– mild elevation in blood pressure (BP)
– an increase in central venous pressure (CVP)
– and essentially no change in cardiac output (CO)
• Accompanied by a redistribution of CO with an
increased proportion going to the brain, heart,
and adrenal glands (diving reflex).

23. • other basic physiologic mechanisms may contribute to
impaired autoregulation-
• Increased expression of inducible and neuronal isoforms
of nitric oxide synthase (iNOS and nNOS), as well as
endothelial NOS, may narrow the autoregulatory window,
• downregulation of prostaglandin receptors in response to
high circulating prostaglandin levels may blunt the
prostaglandin-mediated vasoconstrictive response to
hypertension and thereby contribute to inappropriately
increased cerebral blood flow

24. • With prolonged asphyxia, there can be a loss of
pressure autoregulation and/or CO2
vasoreactivity.
• This, in turn, may lead to further disturbances in
cerebral perfusion, particularly when there is
cardiovascular involvement with hypotension
and/or decreased cardiac output

25. • An inadequate supply of glucose or alternate
substrates plays a pivotal role in hypoxic-ischemic
neuronal cell death.
• Although overall metabolic demands are lower in
the neonatal than in the adult brain, during
periods of rapid brain growth, particularly the
perinatal period, metabolic needs rise.

26. • Brain development is associated with a transition
from the ability to use glucose and ketones as
energy substrates in the neonate to an absolute
requirement for glucose in the adult.
• The immature brain can use lactate as an alternate
fuel source to some degree, and the deleterious
effects of lactate accumulation after hypoxia-
ischemia therefore may be attenuated in the
neonate compared with the adult.

27. • However, normal maturation is characterized by
limitations in glucose transport capacity and
increased use of these alternative fuels such as
lactate.
• The inability to transport glucose across the
blood–brain barrier threatens cerebral glucose
utilization.
• These factors illustrate the importance of
understanding the use of glucose, lactate, and
ketones in the newborn brain under normal and
pathologic conditions

28. • A decrease in cerebral blood flow results in
anaerobic metabolism and eventual cellular
energy failure due to increased glucose utilization
in the brain and a fall in the concentration of
glycogen, phosphocreatine, and adenosine
triphosphate (ATP).

30. • Cellular dysfunction occurs as a result of
diminished oxidative phosphorylation and ATP
production.
• This energy failure impairs ion pump function,
causing accumulation of intracellular Na , Cl ,
H2O, and Ca2 ; extracellular K ; and excitatory
neurotransmitters (e.g., glutamate)

31. Excitotoxicity
• Glutamate can activate a variety of excitatory amino
acid receptors
• Excitatory amino acid neurotransmission plays a
pivotal role in brain development and in learning and
memory.
• substantial body of data has emerged over the past 30
years documenting the fact that overactivation of
excitatory amino acid receptors (i.e., excitotoxicity)
contributes to neurodegeneration in a broad range of
acute and chronic neurologic disorders

32. • Two closely linked mechanisms contribute to
ischemia-induced increases in synaptic glutamate:
– increased efflux from presynaptic nerve terminals
– impaired reuptake by glia and neurons

33. • initial increase in efflux is mediated by a calcium
dependent process through activation of voltage-
dependent calcium channels
• later, calcium-independent efflux is thought to be
mediated primarily by functional reversal of
glutamate transporters.

34. • Removal of glutamate from the synaptic cleft
depends primarily on energy-dependent
glutamate transporters, which are predominantly
glial
• Any pathophysiologic process that depletes energy
supply (e.g., hypoxia-ischemia, hypoglycemia,
prolonged seizures) disrupt these mechanisms and
result in increased synaptic glutamate
accumulation

35. • The NMDA receptor is relatively overexpressed in
the developing brain compared with the adult
brain
• in postnatal day 6–14 rats (which approximates to
the term human neonate), the NMDA receptor is
expressed at 150–200 % of adult levels.
• In humans, receptor expression is significantly
higher at term than in the adult

36. • The predominating combination of subunits in the perinatal
period seems to favor a more prolonged and pronounced
calcium influx.
• In the setting of hypoxia-ischemia, NMDA receptor
overactivation leads to
– massive sodium and water influx
– cell swelling
– elevated intracellular calcium and its associated mitochondrial
dysfunction,
– increased nitric oxide production,
– increased phospholipid turnover
– accumulation of potentially toxic free fatty acids,
– cell death by apoptotic or necrotic mechanisms.
• However, ischemia and energy failure also result in cation
influx by non-NMDA-mediated mechanisms.

38. Oxidative Stress
• Oxidative stress describes the alterations in
cellular milieu that result from an increase in free
radical production as a result of oxidative
metabolism under pathologic conditions
• consequence of mitochondrial dysfunction is an
accumulation of superoxide,

39. • Excitotoxicity causes energy depletion, mitochondrial
dysfunction, and cytosolic calcium accumulation,
the generation of free radicals, such as superoxide,
nitric oxide derivatives, and the highly reactive
hydroxyl radical.
• With reoxygenation, mitochondrial oxidative
phosphorylation is overwhelmed and reactive oxygen
species accumulate
• Intrinsic antioxidant defenses are depleted, and free
radicals directly damage multiple cellular constituents
(lipids, DNA, protein) and can activate pro-apoptotic
pathways.

40. • Contributing factors include a high
polyunsaturated fatty acid content, high level of
lipid peroxidation (particularly in response to
hypoxic stress), immaturity of antioxidant defense
enzymes, and high free iron concentrations,
compared with the adult brain

41. • Nitric oxide metabolism provides critical link
between excitotoxicity and oxidative injury in the
hypoxic ischemic injured brain
• Hypoxic-ischemic increases in nitric oxide
production have multiple potential beneficial and
detrimental effects.
• Nitric oxide regulates vascular tone, influences
inflammatory responses to injury, and directly
modulates NMDA receptor function

42. • Early endothelial NO is protective by maintaining
blood flow, but early neuronal NO and late
inducible NO are neurotoxic by promoting cell
death

43. Inflammation
• Cytokines that have been strongly implicated as
mediators of brain inflammation in neonates
include interleukin (IL)-1b, tumor necrosis factor
(TNF)a, IL-6,and membrane co-factor protein-1
• After an asphyxial episode, there are many
potential sources of plasma cytokines,
– injured endothelium
– acutely injured organs, e.g brain by means of a
disrupted blood–brain barrier

44. Apoptosis
• Apoptosis is critical for normal brain
development, but it is also an important
component of injury following neonatal hypoxia-
ischemia and stroke
• Immediate neuronal death (necrosis) can occur
due to intracellular osmotic overload of Na and
Ca2 , from ion pump failure or excitatory neu-
rotransmitters acting on inotropic receptors (such
as the N-methyl-D-aspartate (NMDA) receptor.

45. • Delayed neuronal death (apoptosis) occurs
secondary to uncontrolled activation of enzymes
and second messenger systems within the cell
– Ca2+-dependent lipases, proteases, and caspases);
– perturbation of mitochondrial respiratory electron
chain transport;
– generation of free radicals and leukotri-enes;
– generation of nitric oxide (NO) through NO synthase;
and depletion of energy stores.

46. • The pattern of injury after hypoxia-ischemia can be
explained in part on the basis of this metabolic
demand;
• brain regions most susceptible to hypoxic-ischemic
injury in the term infant
• subcortical gray matter structures such as the basal
ganglia and thalamus are the same regions that are
most vulnerable to mitochondrial toxins.

47. Neurological Patterns of HIE
• Premature
– Selective subcortical neuronal necrosis
– Periventricular leukomalacia
– Focal/Multifocal ischemic necrosis
– Periventricular hemorrhage/infarction
• Term
– Selective Subcortical Neuronal necrosis
– Status Marmoratusof basal ganglia and thalamus
– Parasagittal cerebral injury
– Focal/Multifocal Ischemic cerebral necrosis

48. DIAGNOSIS
• Assessment
• Low Apgar scores and need for resuscitation in
the delivery room are common but nonspecific
findings
• Many features of the Apgar score relate to
cardiovascular integrity and not neurologic
dysfunction resulting from asphyxia.

49. • the differential diagnosis for a term new-born
with an Apgar score <3 for >10 minutes includes
– depression from maternal anesthesia or analgesia
– trauma
– Infection
– cardiac or pulmonary disorders
– Neuromuscular
– other central nervous system disorders or
malformations
– If the Apgar score is >6 by 5 minutes, perinatal
asphyxia is not likely.

50. Umbilical cord or first blood gas
determination.
• The specific blood gas criteria that define asphyxia
causing brain damage are uncertain
• the pH and base deficit on the cord or first blood
gas is helpful
• In the randomized clinical trials of hypothermia for
neonatal HIE, severe acidosis was defined as pH<7.0
or base deficit <16 mmol/L

51. Clinical Suspicion
• Suspect HIE in encephalopathic newborns with a
history of fetal and neonatal distress and
laboratory evidence of asphyxia.
• Diagnosis not be overlooked in scenarios such as
– meconium aspiration,
– pulmonary hypertension,
– birth trauma
– fetal–maternal hemorrhage

52. • Consider Asphyxia/HIE if -
– 1. Prolonged (>1 hour) antenatal acidosis
– 2. Fetal HR <60 beats/minute
– 3. Apgar score <=3 at >=10 minutes
– 4. Need for positive pressure ventilation for >1 minute
or first cry delayed >5 minutes
– 5. Seizures within 12 to 24 hours of birth
– 6. Burst suppression or suppressed background
pattern on EEG or amplitude-integrated EEG (aEEG)

53. Neurologic Signs
• The clinical spectrum of HIE is described as mild,
moderate, or severe (Sarnat stages of HIE).
• EEG is useful
• Encephalopathy.
– must have depressed consciousness by definition,
whether mild, moderate, or severe.
– 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.

56. Levene Staging
Feature Mild Moderate Severe
Consciousness Irritability Lethargy Comatose
Tone Hypotonia Marked
Hypotonia
Severe
Hypotonia
Seizures No Yes Prolonged
Sucking/Respir
ation
Poor Suck Unable to Suck Unable to
sustain
spontaneous
respiration

57. TOPOGRAPHY OF BRAIN INJURY IN TERM INFANTS WITH HYPOXIC-
ISCHEMIC ENCEPHALOPATHY AND CLINICAL CORRELATES
AREA OF INJURY LOCATION OF INJURY
CLINICAL
CORRELATE(S)
LONG-TERM
SEQUELA(E)
Selective neuronal
necrosis
Entire neuroaxis, deep
cortical area,
brainstem and
pentocubicular
Stupor or coma
Seizures
Hypotonia
Oculomotor
abnormalities
Suck/swallow
abnormalities
Cognitive delay
Cerebral palsy
Dystonia
Seizure disorder
Ataxia
Bulbar and
pseudobulbar palsy
Parasagittal injury
Cortex and subcortical
white matter
Parasagittal regions,
especially posterior
Proximal limb
weakness
Upper extremities
affected more than
lower extremities
Spastic quadriparesis
Cognitive delay
Visual and auditory
processing difficulty

58. Focal ischemic necrosis
Cortex and subcortical
white matter
Vascular injury (usually
middle cerebral artery
distribution)
Unilateral findings
Seizures common and
typically focal
Hemiparesis
Seizures
Cognitive delays
Periventricular injury
Injury to motor tracts,
especially lower
extremity
Bilateral and symmetric
weakness in lower
extremities
More common in
preterm infants
Spastic diplegia

59. • Mild encephalopathy can consist of an apparent
hyperalert or jittery state, but the newborn does
not respond appropriately to stimuli, and thus
consciousness is abnormal.
• Moderate and severe encephalopathies are
characterized by more impaired responses to
stimuli such as light, touch, or even noxious
stimuli.
• The background pattern detected by EEG or aEEG
is useful for determining the severity of
encephalopathy.

60. • Brain stem and cranial nerve abnormalities manifest
as abnormal or absent brain stem reflexes
Pupillary/corneal/oculocephalic/cough/gag
• abnormal eye movements  dysconjugate gaze/
gaze preference/ocular bobbing/absence of visual
fixation or blink to light
• Newborns may show facial weakness (usually
symmetric) and have a weak or absent suck and
swallow with poor feeding.
• They can have apnea or abnormal respiratory
patterns.

61. • Motor abnormalities. With greater severity of
encephalopathy, there is generally greater
hypotonia
• Weakness
• abnormal posture with lack of flexor tone, which
is usually symmetric

62. • Asymmetry in the amount of movement and
posture is a subtle sign of hemiparesis, but it may
be the only focal feature of the examination
• Patients with borderzone parasagittal injury
(ulegyria) tend to have proximal greater than
distal weakness and upper extremity more than
lower extremity weakness (man-in-the-barrel).

63. • A unilateral, focal infarct, especially one involving
the middle cerebral artery, causes contralateral
hemiparesis and focal seizures.
• Patients with selective neuronal necrosis may have
severe hypotonia, stupor, and coma.

64. • Neonates with severe bilateral infarcts may
have quadriparesis.
• Moro and tonic neck reflexes do not
habituate, reflecting the lack of cortical
modulation, which attenuates the response
after repeated trials or sustained stimulus.

65. • Newborns with diencephalic lesions cannot
regulate their temperature and have problems
with sleep-wake cycles.
• The long-term sequelae of focal or multifocal
cerebral necrosis include spastic hemiparesis and
quadriparesis (eg, bilateral hemiparesis),
cognitive deficits, and seizures.
• Persistence of tonic neck reflex posture is a sign
of cortical dysfunction.

66. • With severe HIE, primitive reflexes such as the
Moro or grasp reflex may be diminished
• Over days to weeks, the initial hypotonia may
evolve into spasticity and hyperreflexia if there is
significant HI brain injury
• if a newborn shows significant hypertonia within
the first day or so after birth, the HI insult may
have occurred earlier in the antepartum and
have already resulted in established HI brain
injury.

67. • infants with damage to the corticospinal tract may
have sustained ankle clonus.
• the initial motor manifestation will be flaccid
hypotonia with spasticity later developing.
• Increased active neck and trunk extensor tone are
predictors of quadriparesis.

68. • sign of spasticity that can develop relatively
early is scissoring, where the previously
abducted legs extend, become rigid, and have
extreme hip adduction such that they cross
with stimulation or crying.

69. • Seizures occur in up to 50% of newborns with
HIE, and usually start within 24 hours after the HI
insult.
• Seizures indicate that the severity of
encephalopathy is moderate or severe, not mild.

70. • Seizures may be subtle, tonic, or clonic.
• difficult to differentiate seizures from
jitteriness or clonus, although the latter two
are usually suppressible with firm hold of the
affected limb(s).

71. • Subtle manifestations of neonatal seizures are
confirmed on EEG and include apnea; tonic
eye deviation; sustained eye opening; slow,
rhythmic, tongue thrusting; and boxing,
bicycling, and swimming movements

72. • Being subclinical, EEG remains the gold standard
for diagnosing neonatal seizures, particularly in
HIE.
• Seizures may compromise ventilation and
oxygenation, especially in newborns who are not
receiving mechanical ventilation

73. • Mizrahi and Kellaway suggested the name
brainstem release phenomena because tonic
posturing and some subtle seizure like motor
automatisms are probably the result of primitive
brainstem and spinal motor patterns liberated
because the lack of inhibition from damaged
forebrain structures.
• However, this tonic posturing is not a seizure and,
thus, treatment with antiepileptics does not have
benefit unless the infant is having other
semiology consistent with seizures.

74. Increased intracranial pressure (ICP)
• resulting from diffuse cerebral edema in HIE
often reflects extensive cerebral necrosis
rather than swelling of intact cells and
indicates a poor prognosis.
• Treatment to reduce ICP does not affect
outcome.

75. Multiorgan Dysfunction
• In a minority of cases (<15%), the brain may be
the only organ exhibiting dysfunction following
asphyxia
• The kidney is the most common organ to be
affected
– acute tubular necrosis with oliguria
– water and electrolyte imbalances

76. • Cardiac dysfunction
– caused by transient myocardial ischemia.
– In severely asphyxiated newborns, dysfunction more
commonly affects the right ventricle.
– reduced myocardial contractility
– severe hypotension
– passive cardiac dilatation
– tricuspid regurgitation
– A fixed HR may raise suspicion of severe brain stem injury.
• Gastrointestinal
– bowel ischemia
– necrotizng enterocolitis

77. • Hematologic effects
– disseminated intravascular coagulation
– damage to blood vessels
– poor production of clotting factors due to liver dysfunction
– poor production of platelets by the bone marrow.
• Liver dysfunction
– manifested by isolated elevation of hepatocellular
enzymes
– DIC
– inadequate glycogen stores with resultant hypoglycemia
– altered metabolism
• Pulmonary effects include
– PPHN
– pulmonary hemorrhage
– pulmonary edema due to cardiac dysfunction
– meconium aspiration.

78. • 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.

79. Assessment Tools in HIE
• Amplitude-integrated EEG (aEEG)
– Most useful in infants who have moderate to severe
encephalopathy
• Marginally abnormal or normal aEEG is very
reassuring of good outcome
• Severely abnormal aEEG in infants with moderate
HIE raises the probability of death or severe
disability from 25% to 75%
• Evoked Potentials
– Brainstem auditory evoked potentials, visual evoked
potentials and somatosensory evoked potentials can
be used in full-term infants with HIE
– More sensitive and specific than aEEG alone

80. Neuroimaging
– Cranial ultrasound:
• Not the best in assessing abnormalities in term
infants. Echogenicity develops gradually over days
• most useful for detection of PVL.
• Less useful in assessing edema, subtle midline shift
& posterior fossa hemorrhage & ventricular
compression
– CT: Less sensitive than MRI for detecting
changes in the central gray nuclei
– MRI: Most appropriate technique and is able
to show different patterns of injury. Presence
of signal abnormality in the internal capsule
later in the first week has a very high
predictive value for neurodevelopmental
outcome

81. ACID – BASE MEASUREMENTS
 Assessed by umbilical artery pH measurement
are correlated with neonatal seizures & death
when pH < 7.04.
 Low umbilical – pH may be due to sepsis.
 Association of low pH & long term outcome is
weak.

82. CARDIAC EVALUATION
 Cardiac troponin (CTNI) & troponin T (CTnT).
Cardiac regulatory proteins and are markers of
myocardial damage.
Elevated levels in asphyxia.
 Serum creative kinase myocardial bound:-
(CK-MB) fraction of > 5% to 10% may indicate
myocardial injury

83.  Brain Injury
 CK-BB
 infants within 12 hrs of the insult.
 No specific relation with long term neuro
developmental outcome.
 CK-BB also expressed in placenta, lungs, GIT
and kidneys.
 Renal Evaluation
BUN and serum creatinine may be elevated in
perinatal asphyxia in 2-4 days after the insult.
Urine levels of ß2- microglobulin is used as an
indicator of proximal tubular dysfunction.

84. TREATMENT
• Perinatal management of high-risk
pregnancies
–Fetal HR and rhythm abnormalities may
provide supporting evidence of asphyxia,
especially if accompanied by presence of thick
meconium.
–Measurement of fetal scalp pH is a better
determinant of fetal oxygenation than PO2.
• With intermittent hypoxia-ischemia, PO2 may
improve transiently whereas the pH progressively
falls.

85. • Close monitoring of progress of labor with
awareness of other signs of in utero stress is
important.
• The presence of a constellation of abnormal
findings may indicate the need to mobilize the
perinatal team for a newborn that could require
immediate intervention.

86. Postnatal management
• Ventilation. CO2 should be maintained in the normal
range.
– Hypercapnia can cause cerebral acidosis and cerebral
vasodilation.
– Excessive hypocapnia (CO2 <25 mm Hg) may decrease CBF
• Oxygenation. Oxygen levels should be maintained in
the normal range,
– although poor peripheral perfusion may limit the
accuracy of continuous non-invasive monitoring
– Hypoxemia should be treated with supplemental O2
and/or ventilation.
– Hyperoxia may cause decreased CBF or exacerbate free
radical damage.
Respiratory

87. • Maintain physiologic metabolic state
• Hypocalcemia
• Hypoglycemia
• Hyperglycemiabrain lactate, damage to cellular
integrity, cerebral edema, or further disturbance
in vascular autoregulation.
Metabolic

88. • Temperature. Passive cooling by turning off
warming lights is an effective way to initiate
therapeutic hypothermia as soon as possible after
the HI insult.
– Hyperthermia should always be avoided.

89. Cardiovascular
• Fluid restriction may aid in minimizing cerebral edema
although the effect of uid restriction on long-term
outcome in newborns who are not in renal failure is
not known.
• Judicious fluid managementfluid overload and
inadequate circulating volume to be avoided.
– Fluid overload in asphyxiated newborns
• SIADH secretion hy-ponatremia and hypo-osmolarity in
combination with low urine output and inappropriately
concentrated urine (elevated urine specific gravity, osmolarity, and
Na+).
• ATN

90. • PerfusionCardiovascular stability and
adequate mean systemic arterial BP are to be
maintained
• Dopamine,Milnirone

91. Control of seizures.
• start within 12 hours of birth, increase in
frequency, and then usually resolve within days,
although may persist in severe cases.
• can be extremely difficult to control and may not
be possible to eliminate completely with
currently available anticon-vulsants.
• not yet been proven that improved seizure
control results in improved neurologic outcome

92. • Metabolic perturbations such as hypoglycemia,
hypocalcemia, and hyponatremia that may cause
or exacerbate seizure activity and should be
corrected.

93. • Phenobarbital is the initial drug of choice
• ii. Phenytoin may be added when seizures are not
controlled by phe-nobarbital.
– fosphenytoin can be used
Acute anticonvulsant management

94. • iii. Benzodiazepines are considered third-line
drugs
• iv. Levetiracetam has been used recently because
of its availability in IV form and relative safety and
efficacy for various types of childhood epilepsy.

95. Long-term anticonvulsant
management
• Anticonvulsants can be weaned when the clinical
exam and EEG indicate that the newborn is no
longer h aving seizures.
• If a newborn is receiving more than one
anticonvulsant, weaning should be in the reverse
order of initiation, with phenobarbital being
weaned last.

96. • controversy regarding when phenobarbital should
be discontinued, with some favoring
discontinuation shortly before discharge and
some favoring continued treatment for 1 to 6
months or more

97. Monitoring Of Dysfunction
Organ
Injury
Clinical Signs to
Monitor
Investigations
CNS
Encepha
lopathy
Seizure
Sensorium,Tone,
Cry,abnormal
movements,abn
ormal
relexes,staging
Cranial
USG,EEG,T/MRI

98. Renal
ARF
Myoglobinuria
Uop,Hematria,ede
ma,weight
Serum
Na,K,BUN,Cr,Sp
Gr,R/M
GI
Ileus
NEC
Abdmonial
distension,bowel
sounds,delayed
meconium
passage,gastric
aspirates
Abdomnal X-Ray
when clinical signs
are present
CVS
Myocardial
Ischemia
Papillary Muscle
Necrosis
BP,CFT,HR,Murmur,
crepts,hepatomeg
aly,weight gain
ECG,CxR,ECHO

99. Pulmonary
Meconium
Aspiration
PPHN
RR,Apnea,Chest
retraction,Cyanosis,O
2(FiO2,SaO2)
CxR
ECHO

100. Hematological
DIC
GI Aspirates,
Pulmonary
Hemorrhages,
Petechiae,
Prolonged
bleed from
puncture sites
BT,CT,Plt
cout,PT/INR,aP
TT
Metabolic
Hypogycemia
Hyponatremia(
SIADH)
Hypocalcemia
Metabolic
Acidosis
RBS
Calcium
Na
ABG

101. PROGNOSIS
A. Overall mortality is 10% to 30%.
Neurodevelopment sequelae 15% to 45%.
B. Risk of CP in survivors of perinatal asphyxia is 5% to
10% compared to 0.2% in general population.
 Most CP is not related to perinatal asphyxia & most perinatal
asphyxia does not cams CP.
 Only 3%-13% of infants with CP have evidence of intrapartum
asphyxia

102. C. According to Sarnat staging.
a) Stage 1 – 90% to 1=0% (N) neurologic outcome <
10% mortality.
b) Stage - 2 – 20% to 37% die or have abnormal
neurodevelopmental outcomes.
Infants who exhibit stage 2 sign for > 7 days
have poorer outcomes.

103. c) Stage 3 HIE-50% to 89% die and all survivors
have major neurodevelopment.
d) Prognosis is good if an infant does not
progress to &/or remain in stage 3 & if total
duration of stage 2<5 days.
e) Term baby not breast feeding by Day 10 of life
f) Seizures on Day 1 requiring multiple drugs to
control

104. Outcomes
• depend on the pattern and severity of the brain
injury
• involve motor, visual, and cognitive functions
• follow-up of these newborns should include
assessment of motor function, vision and hearing,
cognition,behavior, and quality of life, through
infancy and childhood

105. • pattern of neurodevelopmental deficits follows an
overt neonatal encephalopathy, often in the
context of a critical illness
• is most commonly associated with the watershed
pattern of injury and white matter damage,
rather than the basal nuclei-predominant pattern
of injury.

106. • (ACOG) Task Force on Neonatal encephalopathy
concluded that an acute intrapartum event could
result in cerebral palsy of the spastic quadriplegic
or dyskinetic type, but could not account for
isolated cognitive deficits

107. Motor Functions
• the risk of cerebral palsy or severe disability may
involve more than one third of affected
newborns
• More in those with severe encephalopathy
• Spastic quadriparesis is the most common type
of CP

108. Vision and Hearing
• Injury to the posterior visual pathway, including the
primary visual cortex, results in “cortical visual
impairment”
• Injuries to the basal nuclei may also affect acuity,
visual fields, or stereopsis (depth perception)
• SNHL, likely secondary to brainstem injury, is also
seen following neonatal encephalopathy affecting 18
percent of survivors of moderate encephalopathy
without cerebral palsy

109. Cognition
• cognitive deficits are seen in 30–50 percent of
childhood survivors
• Cognitive deficits, such as those in language and
memory, may be seen,even when IQ scores are
normal.

110. Brain Imaging and Outcome
• basal nuclei pattern of injury and abnormal signal
intensity in the posterior limb of the internal
capsule are both predictive of severely impaired
motor and cognitive outcomes
• watershed pattern is associated with cognitive
impairments that are not necessarily
accompanied by major motor deficits
– may only be evident after 2 years of age

111. Investigations For Prognosis
• EEG – background burst suppression,low voltage
or electrocerebral silence poor prognosis
• CT/MRI – Diffuse decrease in density on CT scan
at 2-4 weeks of life indicates poor prognosis
• Early MRI – basal ganglia and thalamic
enhancment  poor prognosis

112. Recent advances

114. Therapeutic Cooling
• Extensive experimental data suggest that mild
hypothermia (3-4°C below baseline temperature) applied
within a few hours (no later than 6 h) of injury is
neuroprotective.
• The neuroprotective mechanisms are not completely
understood. Possible mechanisms include
– reduced metabolic rate and energy depletion;
– decreased excitatory transmitter release;
– reduced alterations in ion flux;
– reduced apoptosis due to hypoxic-ischemic encephalopathy
– reduced vascular permeability, edema, and disruptions of
blood-brain barrier functions.

115. • The clinical efficacy of therapeutic hypothermia in
neonates with moderate-to-severe hypoxic-
ischemic encephalopathy has been evaluated in 7
randomized controlled trials.

116. • Criteria from the larger trials (NICHD, CoolCap, and
TOBY) are summarized as follows:
• Near-term infants born at 36 weeks' gestation or more
with birth weight of 1800-2000 g or more, younger than
6 hours at admission
• Evidence of acute event around the time of birth
– Apgar score of 5 or less at 10 minutes after birth
– severe acidosis, defined as pH level of less than 7 or base
deficit of 16 mmol/L or less (cord blood or any blood gas
obtained within 1 h of birth)
– continued need for resuscitation at 10 minutes after birth
– Evidence of moderate to severe encephalopathy at birth

117. • clinical studies have been reassuring thus far
regarding safety and applicability of hypothermia
therapy
• Many theoretical concerns surround hypothermia
and its side effects,
– coagulation defects
– leukocyte malfunctions
– pulmonary hypertension
– worsening of metabolic acidosis
– abnormalities of cardiac rhythm, especially during
rewarming.

118. • Although many components of its
implementation remain to be optimized,
hypothermia therapy is increasingly offered to
infants with moderate-to-severe hypoxic-ischemic
encephalopathy.
•

119. Erythropoietin (Epogen)
• Epogen receptors are present in the developing
human embryo
– higher levels of Epogen in cerebral spinal fluid have
been correlated with improved neurodevelopmental
outcomes.
• may benefit infants with HIE through protection
from neuronal apoptosis, neural regeneration,
decreased inflammation, and decreased
susceptibility to glutamate toxicity.

120. • Term infants with HIE treated with Epogen show
decreased seizure activity, improved EEG results,
and enhanced neurologic outcome.
• Although additional clinical trials are needed,
Epogen appears to be effective in the treatment
of infants with HIE if administered within 48
hours after delivery.

121. • potential adverse reactions associated with
Epogen including hypertension, clotting
abnormalities, seizures, and polycythemia,
though have not been seen in neonates
• 1 study reported an increased incidence of
retinopathy of prematurity in premature infants
treated with Epogen

122. Magnesium sulfate (MgSO4
• Magnesium sulfate is an N-methyl-D-aspartate
receptor antagonist.
• N-methyl-D-aspartate is a receptor for glutamate,
an amino acid important in cell proliferation,
differential, and survival in the developing brain.

123. • Conflicting data exist regarding the effectiveness
of MgSO4 as a neuroprotective agent.
• Prenatal administration of MgSO4 to mothers at
risk for preterm delivery is associated with
reduced incidence of cerebral palsy at 3 years and
improved neurodevelopmental outcomes
• When MgSO4 was administered postnatally to
term infants with HIE, there was no improvement
in their amplitude-integrated EEG, and when
administered in large doses, MgSO4 can cause
profound hypotension.[26]

124. Allopurinol
• Allopurinol is an antioxidant that inhibits
formation of the free radicals that play such a
significant role in the cellular damage associated
with HIE.
• when term infants with HIE received allopurinol
within 3 hours after birth, there was less free
radical formation.

125. • Administration of allopurinol to mothers whose
pregnancies are complicated by fetal hypoxia, has
been associated with improved cord gases

126. Stem Cells
• Stem cell transplantation may minimize the
effect of HIE by replacing damaged cells,
promoting cell regeneration, inhibiting
inflammation, and releasing trophic factors
that heal and improve cell survival
• Efficacy of stem cell transplantation, however,
appears dependent on timing of implantation,
and this therapeutic window is presently
unknown.

127. THANK YOU

131. • Neurologic Findings
• Cranial nerves
• Lack of reflex activity mediated by the cranial nerves can indicate brainstem dysfunction.
• Full-term infants should blink and sustain eye closure in response to a sustained light stimulus. Repeated
flashes of light should produce habituation (eg, attenuated blinking) after 3-4 stimuli. Virtually all full-term
newborns can track a ball of red wool, and the movement of stripes of at least one eighth of an inch or
bigger can elicit opticokinetic nystagmus. Objects and pictures with round contours and facial appearances
also make good targets for tracking in the newborn. Tracking is possible in infants with complete
destruction of the occipital cortex by virtue of a subcortical pulvinar-collicular system. Retinal hemorrhages
are commonly observed in the neonate after vaginal delivery and can result in decreased pupil response.
Destruction of the occipital cortex will also not affect pupillary response, because the responsible pathways
leave the optic nerve and travel to the Edinger-Westphal nucleus, which sends back axons via the bilateral
oculomotor nerves (consensual pupillary reflex).
• Neurologic examination may be difficult in the small and frail premature infant, but weakness of the lower
extremities sometimes reflects the neuropathologic substrate of periventricular leukomalacia. Over time,
the patient with periventricular white-matter lesions develops spastic diplegia affecting the lower
extremities more than the upper extremities.
• Blinking to light starts at 26 weeks’ gestational age, sustained eye closure to light is seen around 32 weeks,
and 90% of newborns track a ball of red wool by 34 weeks. Opticokinetic reflexes can be seen at 36 weeks.
The pupil starts reacting to light around 30 weeks, but the light reflex is not consistently assessable until the
gestational age of 32-35 weeks. Pupillary reflexes are reliably present at term. Extraocular movements can
be elicited by performing the doll's-eye maneuver at 25 weeks’ gestation and by performing caloric
stimulation at 30 weeks’ gestation.
• In infants aged 32-34 weeks’ gestation, suck and swallow are reasonably coordinated with breathing, but
the actions are not perfected until after term.
• Patients with mild HIE-NE often have mydriasis. Progression of the disease may produce miosis (even in the
dark) responsive to light, and in severe cases (stage 3 of Sarnat classification), the pupils are small or
midpositioned and poorly reactive to light, reflecting sympathetic or parasympathetic dysfunction.
• The lack of pupillary, eye movement, corneal, gag, and cough reflexes may reflect damage to the brainstem,
where the cranial-nerve nuclei are located. Decreased respiratory drive or apnea can be from lesions of the
respiratory center, which overlap with vagal nuclei (ambiguous and solitaire) or medullary reticular
formation. Ventilatory disturbances in HIE may manifest as periodic breathing apnea (similar to Cheyne-
Stokes respiration) or just decreased respiratory drive

132. • Motor function
• Begin the motor examination of an infant with suspected HIE-NE by qualitatively and quantitatively observing his or her posture and
spontaneous movements. Asymmetry in the amount of movement and posture is a subtle sign of hemiparesis, but it may be the only
focal feature of the examination. Slight stimulation (eg, gently touching the patient) can increase motor activity in the term neonate and
may be helpful in demonstrating asymmetrical hemiparesis.
• Eliciting the Moro reflex may be an excessive stimulus and mask a subtle asymmetry in limb movement. Asymmetry in the Moro reflex
is seen in peripheral lesions (eg, those due to brachial plexus injury).
• Total absence or paucity of spontaneous movements, especially if associated with no reaction to painful stimuli and generalized
hypotonia, indicates brainstem dysfunction or severe, diffuse, or multifocal cortical damage.
• Specific patterns of motor weakness indicate cerebral injury patterns. Patients with borderzone parasagittal injury (ulegyria) tend to
have proximal greater than distal weakness and upper extremity more than lower extremity weakness (man-in-the-barrel). A unilateral,
focal infarct, especially one involving the middle cerebral artery, causes contralateral hemiparesis and focal seizures. Patients with
selective neuronal necrosis may have severe hypotonia, stupor, and coma.
• Motor examination of a newborn with large unilateral lesions may reveal mild hemiparesis and seizures in as many as 80%. The seizures
are often partial (focal) and contralateral to the cortical lesion. Neonates with severe bilateral infarcts may have quadriparesis. Moro
and tonic neck reflexes do not habituate, reflecting the lack of cortical modulation, which attenuates the response after repeated trials
or sustained stimulus. Newborns with diencephalic lesions cannot regulate their temperature and have problems with sleep-wake
cycles. The long-term sequelae of focal or multifocal cerebral necrosis include spastic hemiparesis and quadriparesis (eg, bilateral
hemiparesis), cognitive deficits, and seizures.
• Foot-ankle dorsiflexion or triple flexion (eg, foot-ankle dorsiflexion, knee and hip flexion) after plantar stimulation reflects only an intact
spinal cord and sensory and motor nerves. Extensor movements (eg, arm elevation above the level of the shoulders) are more
sophisticated motor actions than the dorsiflexion or triple flexion and require some cortical function.
• A tonic neck reflex is performed by turning the patient's head to one side. The patient demonstrates arm and leg extension on the side
to which the head is turned and flexion on the opposite side (fencer's posture). The tonic neck reflex posture should go away after
several seconds, and its persistence is a sign of cortical dysfunction.
• Spasticity is a velocity-dependent increase in tone that is generally most prominent with limb extension in muscle groups with
antigravitational action (arm flexion, plantar extension). This sign can be seen over time in infants with corticospinal tract damage
caused by a hypoxic-ischemic insult. In the neonatal period, spasticity is commonly noted first and is most prominent in the distal parts
of the extremities. All fingers are flexed with the thumb under the second to fifth fingers, a pattern commonly referred to as cortical
thumbs. Fewer than 5-10 beats of ankle clonus may be present in healthy neonates, but infants with damage to the corticospinal tract
may have sustained ankle clonus. However, the initial motor manifestation will be flaccid hypotonia with spasticity later developing.
• When assessing muscle tone, the state of arousal and prematurity must be taken into account. In the acute phase, tone is decreased in
a generalized fashion affecting trunk and extremities. The flexor tone in the limbs is best assessed in term infants by showing a
discrepancy in the scoring system between Dubowitz neurologic examination and morphologic examination. The infant looks like a “rag
doll” when supported by a hand under the chest (vertical suspension). Head lag is demonstrated by traction of the hands in a supine
position. The infant folds around the examiner's hand when lifted prone with a hand supporting the chest (horizontal suspension).
• Hip abduction may be seen with increased tone and even with decerebrate posturing (frog-leg posture). Another manifestation of CNS
dysfunction in the neonatal period is increased axial extensor tone with arching of the back and neck extension or opisthotonus. Many
infants simultaneously have decreased axial flexor tone (eg, major head lag on arm traction maneuver) and increased axial extensor
tone. In many cases, limb and axial hypotonia are present for several months before increased axial extensor tone or limb spasticity can
be detected. Increased active neck and trunk extensor tone are predictors of quadriparesis. Another sign of spasticity that can develop
relatively early is scissoring, where the previously abducted legs extend, become rigid, and have extreme hip adduction such that they
cross with stimulation or crying.

133. • .
• Seizures
• HIE is often reported to be the most frequent cause of neonatal seizures. They usually occur 12-24 hours after birth and are difficult to control with
anticonvulsants. Large, unilateral infarcts occur with neonatal seizures in as many as 80% of patients. Seizures are often partial (focal) and
contralateral to the cortical lesion. About two thirds of newborns with cerebral venous infarcts have seizures. Those with multiple or diffuse lesions
and cerebral venous infarcts often have multifocal or migratory seizures. Seizures are observed during physical examination and may confirm the
diagnosis. Observation often reveals clonic rhythmic contractions. When holding the limb affected by clonic seizures, the examiner's hand shakes or
feels limb movement. Limb flexion or extension does not suppress the clonic activity, as it does in jitteriness and clonus. Newborn infants cannot
have generalized seizures due to immaturity of the neuronal pathways connecting the 2 halves of the brain.
• Tonic, unilateral, or focal seizures consistently have an EEG signature. In the seizures, unilateral arm and leg posturing is often accompanied by
ipsilateral trunk flexion. Generalized tonic posturing (eg, extension of the upper and lower extremities or extension of the legs and flexion of the
arms) is related to an EEG seizure in 15% of affected neonates.
• Tonic seizures can be seen in neonates with local anesthetic intoxication. Although generalized tonic posturing is infrequently associated with
electrical seizures, it is not a benign sign. Of neonates with tonic posturing and an abnormal EEG background, 13% have normal development.
• Subtle seizures may be a part of the HIE-NE picture. Subtle manifestations of neonatal seizures are confirmed on EEG and include apnea; tonic eye
deviation; sustained eye opening; slow, rhythmic, tongue thrusting; and boxing, bicycling, and swimming movements. Most still accept that some
subtle seizures may be correlated with EEG results. However, publications since the late 1980s have shown that seizures are not as frequent as
previously thought and that they are unusual in patients close to term. Several other patterns of subtle neonatal seizures are described without EEG
confirmation. The lack of an EEG signature does not exclude CNS pathology because neonates with HIE often have motor automatisms without EEG
seizures. Management is controversial, but treatment is not usually beneficial unless more overt seizure activity is noted.[31]
• Seizures may be difficult to clinically diagnose in the premature neonate. Subtle seizures associated with ictal EEG changes are not rare in premature
infants. The subtle patterns of neonatal seizures in the premature infant include sustained eye opening, oral-buccal-lingual movements (smacking,
drooling, chewing), pedaling movements, grimacing, and autonomic manifestations.[#sarnat]