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PERINATAL ASPHYXIA
(HYPOXIC ISCHEMIC
(ENCEPHALOPATHY
DR. TAI AL AKAWY
Perinatal asphyxia
 Perinatal asphyxia, more appropriately known
as hypoxic-ischemic encephalopathy, is
characterized by ...
 Severe hypoxia results in anaerobic glycolysis
and lactic acid production first in the peripheral
tissues (muscle and he...
 Hypoxia and acidosis can depress myocardial
function, leading to hypotension and ischemia.
 Ischemia can impair oxygen ...
TIMING OF INJURY
 Asphyxia can occur before, during, or after
birth. Based on a review of multiple studies
that have exam...
 Antepartum events, such as maternal
hypotension or trauma, account for 4 to 20
percent of cases.
 Intrapartum events, s...
 In approximately 10 percent of cases, a
postnatal insult occurs, usually caused by
severe cardiopulmonary abnormalities ...
 Neonatal encephalopathy is a heterogeneous
syndrome characterized by signs of central
nervous system dysfunction in newb...
 Clinical suspicion of neonatal encephalopathy
should be considered in any newborn
exhibiting an abnormal level of consci...
 "Neonatal encephalopathy" has emerged as
the preferred term to describe central nervous
system dysfunction in the newbor...
 While neonatal encephalopathy was once
automatically ascribed to hypoxia-ischemia
 It is now known that hypoxia-ischemi...
 Some investigators require stringent criteria
for using the term neonatal encephalopathy,
such as two or more symptoms o...
 However, the use of Apgar scores alone is
problematic, as Apgar scores may be low due
to maternal analgesia or prematuri...
 Given that the underlying nature of brain injury
causing neurologic impairment in a newborn is
often poorly understood, ...
 The incidence of neonatal encephalopathy
depends on how the syndrome is defined, but
varies between two to nine per 1000...
 Despite major advances in monitoring
technology and knowledge of fetal and
neonatal pathologies, perinatal asphyxia or,
...
Pathophysiology
 Brain hypoxia and ischemia due to systemic
hypoxemia, reduced cerebral blood flow
(CBF), or both are the...
 The initial compensatory adjustment to an
asphyxial event is an increase in CBF due to
hypoxia and hypercapnia.
 This i...
 A blood pressure (BP) increase due to
increased release of epinephrine further
enhances this compensatory response.
Fetal response to asphyxia illustrating the initial redistribution of blood
flow to vital organs. With prolonged asphyxial...
 In adults, CBF is maintained at a constant
level despite a wide range in systemic BP.
 This phenomenon is known as the ...
 Limited data in the human fetus and the
newborn infant suggest that CBF is stable
over much narrower range of BPs
 Some...
 In addition, the autoregulatory zone may also
be set at a lower level, about the midpoint of
the normal BP range for the...
 In the fetus and newborn suffering from acute
asphyxia, after the early compensatory
adjustments fail, the CBF can becom...
 As BP falls, CBF falls below critical levels, and
the brain injury secondary to diminished blood
supply and a lack of su...
 During the early phases of brain injury, brain
temperature drops, and local release of
neurotransmitters, such as gamma-...
 At the cellular level, neuronal injury in hypoxic-
ischemic encephalopathy is an evolving
process.
 The magnitude of th...
At the biochemical level
 Excitatory amino acid (EAA) receptor
overactivation plays a critical role in the
pathogenesis o...
 This results in high synaptic levels of
glutamate and EAA receptor overactivation,
including N-methyl-D-aspartate (NMDA)...
 Accumulation of Na+
coupled with the failure of
energy dependent enzymes such as Na+/
K+
-ATPase leads to rapid cytotoxi...
 EAAs accumulation also contributes to
increasing the pace and extent of programmed
cell death through secondary Ca++
int...
 Finally, developing oligo/dendroglia is uniquely
susceptible to hypoxia-ischemia, specifically
excito-toxicity and free ...
 During the reperfusion period, free radical
production increases due to activation of
enzymes such as cyclooxygenase, xa...
 Free radicals can lead to lipid peroxidation as
well as DNA and protein damage and can
trigger apoptosis.
 Finally, fre...
 This excessive NO production plays an
important role in the pathophysiology of
perinatal hypoxic-ischemic brain injury.
...
 Following the initial phase of energy failure
from the asphyxial injury, cerebral metabolism
may recover following reper...
 This new phase of neuronal damage, starting
at about 6-24 hours after the initial injury, is
characterized by mitochondr...
 The duration of the delayed phase is not
precisely known in the human fetus and
newborn but appears to increase over the...
Pathophysiology of hypoxic-ischemic brain injury in the developing brain. During the
initial phase of energy failure, glut...
Frequency
 In the United States and in most advanced
countries, the incidence of hypoxic-ischemic
encephalopathy is 1-8 c...
Mortality/Morbidity
 In severe hypoxic-ischemic encephalopathy,
the mortality rate is reportedly 25-50%. Most
deaths occu...
 80% of infants who survive severe hypoxic-
ischemic encephalopathy develop serious
complications,
 10-20% develop moder...
History
 The 1996 guidelines from the AAP and ACOG for
(HIE) indicate that all of the following must be present
for the d...
CNS Manifestations
Mild hypoxic-ischemic encephalopathy
 Muscle tone may be slightly increased and
deep tendon reflexes m...
Moderately severe hypoxic-
ischemic encephalopathy
 The infant is lethargic, with significant
hypotonia and diminished de...
 An initial period of well-being or mild hypoxic-
ischemic encephalopathy may be followed by
sudden deterioration, sugges...
Severe hypoxic-ischemic
encephalopathy
 Stupor or coma is typical. The infant may not
respond to any physical stimulus.
...
 Disturbances of ocular motion. The pupils may
be dilated, fixed, or poorly reactive to light
 Seizures occur early and ...
 As the injury progresses, seizures subside and
the EEG becomes isoelectric or shows a burst
suppression pattern.
 At th...
Infants who survive severe
hypoxic-ischemic encephalopathy
 The level of alertness improves by days 4-5 of
life.
 Hypoto...
Multiorgan Dysfunction
 Multiorgan systems involvement is a hallmark
of hypoxic-ischemic encephalopathy.
 Heart (43-78%)...
 Renal (46-72%)
Renal failure presents as oliguria, leading to
significant water and electrolyte imbalances.
 Liver(80-8...
 Hematologic (32-54%)
Disturbances include increased nucleated
RBCs, neutropenia or neutrophilia,
thrombocytopenia, and c...
Neurologic Findings
Cranial nerves
 Lack of reflex activity mediated by the cranial
nerves can indicate brainstem dysfunc...
 The pupil starts reacting to light around 30
weeks, but the light reflex is not consistently
assessable until the gestat...
 Patients with mild HIE often have mydriasis.
Progression of the disease may produce
miosis responsive to light, and in s...
 The lack of pupillary, eye movement, corneal,
gag, and cough reflexes may reflect damage
to the brainstem, where the cra...
Motorfunction
 Begin the motor examination of an infant with
suspected HIE by qualitatively and
quantitatively observing ...
Se iz ure s
 HIE is often reported to be the most frequent
cause of neonatal seizures
 They usually occur 12-24 hours af...
Sarnat Staging System
 The staging system proposed by Sarnat in
1976 is often useful in classifying the degree
of encepha...
Causes
 Badawi et al investigated risk factors of neonatal
encephalopathy in the Western Australian case
control study.
...
Riskfactors forneonatal encephalopathy.
Laboratory Studies
 There are nor specific tests to confirm or
exclude a diagnosis of hypoxic-ischemic
encephalopathy (HI...
 Serum electrolyte levels
 In severe cases, daily assessment of serum
electrolytes are valuable until the infant's
statu...
 Renal function studies
Serum creatinine levels, creatinine clearance,
and BUN levels suffice in most cases.
 Cardiac an...
 Coagulation system evaluation
This includes prothrombin time, partial
thromboplastin time, and fibrinogen levels.
 ABG
...
Medical Care
 Following initial resuscitation and stabilization,
treatment of (HIE) is largely supportive and
should focu...
Supportive Care in Patients with
Hypoxic-ischemic Encephalopathy
 Most infants with severe hypoxic-ischemic
encephalopath...
 Of note, recent evidence indicates that
increased FiO2 in the first 6 hours of life is a
significant risk factor for adv...
Perfusion and Blood Pressure
Management
 Studies indicate that a mean blood pressure
(BP) above 35-40 mm Hg is necessary ...
Fluid and Electrolytes
Management
 Because of the concern for acute tubular
necrosis (ATN) and syndrome of inappropriate
...
 However, fluid and electrolyte management
must be individualized on the basis of clinical
course, changes in weight, uri...
 The role of prophylactic theophylline, given
early after birth, in reducing renal dysfunction
after HIE has been evaluat...
 Fluid and glucose homeostasis should be
achieved.
 Avoid hypoglycemia and hyperglycemia
because both may accentuate bra...
Treatment of Seizures
 Hypoxic-ischemic encephalopathy is the most
common cause of seizures in the neonatal
period.
 Sei...
Hypothermia Therapy
 Extensive experimental data suggest that mild
hypothermia (3-4°C below baseline
temperature) applied...
 Possible mechanisms include
(1) reduced metabolic rate and energy
depletion;
(2) decreased excitatory transmitter releas...
 The clinical efficacy of therapeutic
hypothermia in neonates with moderate-to-
severe hypoxic-ischemic encephalopathy ha...
Inclusion criteria))RCT
 Near-term infants
 Evidence of acute event around the time of
birth - Apgar score of 5 or less ...
at least 2 of the following:
lethargy, stupor, or coma;
abnormal tone or posture;
abnormal reflexes [suck, grasp, Moro, ga...
Randomized controlled trials of therapeutic hypothermia formoderate-to-severe
hypoxic-ischemic encephalopathy (HIE).
the results of the trials
 No difference in composite outcome of death
or severe disability were noted between the
groups...
 These clinical studies have been reassuring
regarding safety and applicability of
hypothermia therapy
 Therapeutic hypo...
hypothermia and its side effects
 include coagulation defects,
 leukocyte malfunctions,
 pulmonary hypertension,
 wors...
What is the optimal timing of
initiation of hypothermia therapy?
 Cooling must begin early, within 6 hours of
injury. How...
6hr???!!!>
 On the other hand, a favorable outcome may
be possible if the cooling begins beyond 6
hours after injury.
 A...
What is the optimal duration of
hypothermia therapy?
 The greater the severity of the initial injury, the
longer the dura...
What is the best method?
 Two methods have been used in clinical trials:
selective head cooling and whole body
cooling.
selective head cooling
 In selective head cooling, a cap (CoolCap)
with channels for circulating cold water is
placed ove...
whole body hypothermia
 In whole body hypothermia, the infant is
placed on a commercially available cooling
blanket, thro...
What is the optimal rewarming
method?
 Rewarming is a critical period.
 In clinical trials, rewarming was carried out
gr...
Does hypothermia therapy result in
long-termbenefits?
 Several meta-analysis have been conducted
and indicate that therap...
In a Cochrane review, Jacobs et al found that
therapeutic hypothermia results in significant
reduction in the following:
...
 They also found a significant increase in
thrombocytopenia, although it was not
clinically significant.
 Benign sinus b...
 Hypothermia therapy should be conducted
under strict protocols and reserved to regional
referral centers offering compre...
NEUROPROTECTIVE
STRATEGIES
Summary of potential neuroprotective strategies
Promising avenues include the
following:
 Prophylactic barbiturates: high-dose
phenobarbital (40 mg/kg) was given over 1
...
 Erythropoietin: In a recent study, low-dose
erythropoietin (300-500 U/kg) administered for
2 weeks starting in the first...
 Allopurinol: Slight improvements in survival
and cerebral blood flow (CBF) were noted in a
small group of infants tested...
 Excitatory amino acid (EAA) antagonists: (MK-
801, an EAA antagonist), has shown
promising results in experimental anima...
Medication Summary
 Providing standard intensive care support,
correcting metabolic acidosis, close monitoring
of the flu...
FurtherInpatient Care
 Close physical therapy and developmental
evaluations are needed prior to discharge in
patients wit...
References
 Ferriero DM. Neonatal brain injury. NEng lJ Me d. Nov 4 2004;351(19):1985-95. [Medline].
 Perlman JM. Brain ...
References
 Papile LA, Rudolph AM, Heymann MA. Autoregulation of cerebral blood flow in the preterm fetal lamb.Pe dia tr
...
THANK YOU
Case presentation
 A male , post term (42)W , NVD, AGA , BW
3.625, admitted to our NICU at 12:15 am with
a diagnosis of H...
Natal History
 Spontaneous vaginal delivery , spont. Rupture
of memb.,clear amnion , vertex presentation ,
fetal monitori...
ABG cord blood result:
 PH 6.8
 Pco2 : 72
 Po2 : 27
 Hco3
 BE -14
 Whole body cooling was started at 12:30 am
(within 15 min of birth)
 Monitoring of pulse, temp, bl press and ECG
cardia...
COOLING for 72hr
 On D 2 : prolonged PT 50 sec and PTT 2 min
for which plasma trnsfusion was given
 Erythropoietin inj. ...
 D5: significant apnea attacks , PTV was given
then NCPAP ( peep 5 , fio2 30%)
 Hypoactive , poor reflexes
 BP monitori...
 D7: nasal pronge ( stop NCPAP)
 Full fontanelle: CSF analysis (bloody tap)
 Cr U/S : free
 MRI : pic. Of cerebral oed...
 D8: ECG monitor multiple premature
ventricular contractions associated with
generalized tonic convulsions treated with I...
Discharge plan:
 Educate the parent about NG feeding with
gradual stimulation of oral suckling ( pacifiers)
 Follow up a...
 Fundus exam and hearing assessment to
exclude potential handicap
 Follow up of developmental mile stones
Perinatal asphyxia
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Perinatal asphyxia

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PERINATAL ASPHYXIA, hypoxic ischemic encephalopathy
Dr.Tai Al Akawy
Consultant pediatrician @ Alexandria University Children Hospital

Published in: Health & Medicine
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Perinatal asphyxia

  1. 1. PERINATAL ASPHYXIA (HYPOXIC ISCHEMIC (ENCEPHALOPATHY DR. TAI AL AKAWY
  2. 2. Perinatal asphyxia  Perinatal asphyxia, more appropriately known as hypoxic-ischemic encephalopathy, is characterized by clinical and laboratory evidence of acute or subacute brain injury due to asphyxia.  The primary causes of this condition are systemic hypoxemia and/or reduced cerebral blood flow (CBF).  Birth asphyxia causes 23% of all neonatal deaths worldwide.
  3. 3.  Severe hypoxia results in anaerobic glycolysis and lactic acid production first in the peripheral tissues (muscle and heart) and then in the brain.  Ischemia (lack of sufficient blood flow to all or part of an organ) is both a cause and a result of hypoxia.
  4. 4.  Hypoxia and acidosis can depress myocardial function, leading to hypotension and ischemia.  Ischemia can impair oxygen delivery, causing further compromise, as well as disrupt delivery of substrate and removal of metabolic and respiratory by-products (eg, lactic acid, carbon dioxide).
  5. 5. TIMING OF INJURY  Asphyxia can occur before, during, or after birth. Based on a review of multiple studies that have examined the temporal relationship of obstetric events and neonatal outcomes, predominantly HIE in term infants, the proportion of conditions that occurs in each time period can be estimated
  6. 6.  Antepartum events, such as maternal hypotension or trauma, account for 4 to 20 percent of cases.  Intrapartum events, such as placental abruption or umbilical cord prolapse, are seen in 56 to 80 percent.
  7. 7.  In approximately 10 percent of cases, a postnatal insult occurs, usually caused by severe cardiopulmonary abnormalities or associated with prematurity.  However, the timing of injury often is difficult to establish for an individual infant
  8. 8.  Neonatal encephalopathy is a heterogeneous syndrome characterized by signs of central nervous system dysfunction in newborn infants
  9. 9.  Clinical suspicion of neonatal encephalopathy should be considered in any newborn exhibiting an abnormal level of consciousness, seizures, tone and reflex abnormalities, apnea, aspiration and feeding difficulties
  10. 10.  "Neonatal encephalopathy" has emerged as the preferred term to describe central nervous system dysfunction in the newborn period  The terminology does not imply a specific underlying pathophysiology since the nature of brain injury causing neurologic impairment in a newborn is poorly understood.
  11. 11.  While neonatal encephalopathy was once automatically ascribed to hypoxia-ischemia  It is now known that hypoxia-ischemia is only one of many possible contributors to neonatal encephalopathy.  Whether a particular newborn's encephalopathy can be attributed to hypoxic- ischemic brain injury is often unclear.
  12. 12.  Some investigators require stringent criteria for using the term neonatal encephalopathy, such as two or more symptoms of encephalopathy lasting over 24 hours ,while others require no more than a low five minute Apgar score
  13. 13.  However, the use of Apgar scores alone is problematic, as Apgar scores may be low due to maternal analgesia or prematurity, or can be normal in the presence of acute hypoxia- ischemic injury.
  14. 14.  Given that the underlying nature of brain injury causing neurologic impairment in a newborn is often poorly understood, "neonatal encephalopathy" has emerged as the preferred terminology to describe central nervous system dysfunction in the newborn period, as it does not imply a specific underlying pathophysiology
  15. 15.  The incidence of neonatal encephalopathy depends on how the syndrome is defined, but varies between two to nine per 1000 term births  As the term “neonatal encephalopathy” has become increasingly favored, it has been shown that the diagnosis of "birth asphyxia" has declined over the past decade
  16. 16.  Despite 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 that causes significant mortality and long-term morbidity.
  17. 17. Pathophysiology  Brain hypoxia and ischemia due to systemic hypoxemia, reduced cerebral blood flow (CBF), or both are the primary physiological processes that lead to hypoxic-ischemic encephalopathy
  18. 18.  The initial compensatory adjustment to an asphyxial event is an increase in CBF due to hypoxia and hypercapnia.  This is accompanied by a redistribution of cardiac output to essential organs, including the brain, heart, and adrenal glands.
  19. 19.  A blood pressure (BP) increase due to increased release of epinephrine further enhances this compensatory response.
  20. 20. Fetal response to asphyxia illustrating the initial redistribution of blood flow to vital organs. With prolonged asphyxial insult and failure of compensatory mechanisms, cerebral blood flow falls, leading to ischemic brain injury.
  21. 21.  In adults, CBF is maintained at a constant level despite a wide range in systemic BP.  This phenomenon is known as the cerebral autoregulation, which helps maintain cerebral perfusion  In human adults, the BP range at which CBF is maintained is 60-100 mm Hg.
  22. 22.  Limited data in the human fetus and the newborn infant suggest that CBF is stable over much narrower range of BPs  Some experts have postulated that, in the healthy term newborn, the BP range at which the CBF autoregulation is maintained may be only between 10-20 mm Hg (compared with the 40 mm Hg range in adults)
  23. 23.  In addition, the autoregulatory zone may also be set at a lower level, about the midpoint of the normal BP range for the fetus and newborn.  However, the precise upper and lower limits of the BP values above and below which the CBF autoregulation is lost remain unknown for the human newborn.
  24. 24.  In the fetus and newborn suffering from acute asphyxia, after the early compensatory adjustments fail, the CBF can become pressure-passive, at which time brain perfusion depends on systemic BP
  25. 25.  As BP falls, CBF falls below critical levels, and the brain injury secondary to diminished blood supply and a lack of sufficient oxygen occurs.  This leads to intracellular energy failure.
  26. 26.  During the early phases of brain injury, brain temperature drops, and local release of neurotransmitters, such as gamma- aminobutyric acid transaminase (GABA), increase.  These changes reduce cerebral oxygen demand, transiently minimizing the impact of asphyxia.
  27. 27.  At the cellular level, neuronal injury in hypoxic- ischemic encephalopathy is an evolving process.  The magnitude of the final neuronal damage depends on duration and severity of the initial insult combined to the effects of reperfusion injury, and apoptosis.
  28. 28. At the biochemical level  Excitatory amino acid (EAA) receptor overactivation plays a critical role in the pathogenesis of neonatal hypoxia-ischemia.  During cerebral hypoxia-ischemia, the uptake of glutamate (the major excitatory neurotransmitter of the mammalian brain) is impaired.
  29. 29.  This results in high synaptic levels of glutamate and EAA receptor overactivation, including N-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methyl-4 isoxazole propionate (AMPA), and kainate receptors.  NMDA receptors are permeable to Ca++ and Na+ , whereas AMPA and kainate receptors are permeable to Na+
  30. 30.  Accumulation of Na+ coupled with the failure of energy dependent enzymes such as Na+/ K+ -ATPase leads to rapid cytotoxic edema and necrotic cell death.  Activation of NMDA receptor leads to intracellular Ca++ accumulation and further pathologic cascades activation.
  31. 31.  EAAs accumulation also contributes to increasing the pace and extent of programmed cell death through secondary Ca++ intake into the nucleus.
  32. 32.  Finally, developing oligo/dendroglia is uniquely susceptible to hypoxia-ischemia, specifically excito-toxicity and free radical damage.  This white matter injury may be the basis for the disruption of long-term learning and memory abilities in infants with hypoxic- ischemic encephalopathy.
  33. 33.  During the reperfusion period, free radical production increases due to activation of enzymes such as cyclooxygenase, xanthine oxidase, and lipoxygenase.  Free radical damage is further exacerbated in the neonate because of immature antioxidant defenses..
  34. 34.  Free radicals can lead to lipid peroxidation as well as DNA and protein damage and can trigger apoptosis.  Finally, free radicals can combine with nitric oxide (NO) to form peroxynitrite a highly toxic oxidant
  35. 35.  This excessive NO production plays an important role in the pathophysiology of perinatal hypoxic-ischemic brain injury.  Inflammatory mediators (cytokines and chemokines) have been implicated in the pathogenesis of HIE and may represent a final common pathway of brain injury.
  36. 36.  Following the initial phase of energy failure from the asphyxial injury, cerebral metabolism may recover following reperfusion, only to deteriorate in a secondary energy failure phase.
  37. 37.  This new phase of neuronal damage, starting at about 6-24 hours after the initial injury, is characterized by mitochondrial dysfunction, and initiation of the apoptotic cascade.  This phase has been called the "delayed phase of neuronal injury."
  38. 38.  The duration of the delayed phase is not precisely known in the human fetus and newborn but appears to increase over the first 24-48 hours and then start to resolve thereafter.  In the human infant, the duration of this phase is correlated with adverse neurodevelopmental outcomes at 1 year and 4 years after insult.
  39. 39. Pathophysiology of hypoxic-ischemic brain injury in the developing brain. During the initial phase of energy failure, glutamate mediated excitotoxicity and Na+/K+ ATPase failure lead to necrotic cell death. Aftertransient recovery of cerebral energy metabolism, a secondary phase of apoptotic neuronal death occurs.(ROS = Reactive
  40. 40. Frequency  In the United States and in most advanced countries, the incidence of hypoxic-ischemic encephalopathy is 1-8 cases per 1000 births.  The incidence of HIE is reportedly high in countries with limited resources; however, precise figures are not available.  Birth asphyxia is the cause of 23% of all neonatal deaths worldwide.
  41. 41. Mortality/Morbidity  In severe hypoxic-ischemic encephalopathy, the mortality rate is reportedly 25-50%. Most deaths occur in the first week of life due to multiple organ failure.  Some infants with severe neurologic disabilities die in their infancy from aspiration pneumonia or systemic infections.
  42. 42.  80% of infants who survive severe hypoxic- ischemic encephalopathy develop serious complications,  10-20% develop moderately serious disabilities, and  as many as 10% are healthy.
  43. 43. History  The 1996 guidelines from the AAP and ACOG for (HIE) indicate that 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, if obtained  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)
  44. 44. CNS Manifestations 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, or excessive crying or sleepiness, may be observed.  The neurologic examination findings normalize by 3-4 days of life.
  45. 45. 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.  Occasional periods of apnea.  Seizures may occur within the first 24 hours of life.  Full recovery within 1-2 weeks is possible and is associated with a better long-term outcome.
  46. 46.  An initial period of well-being or mild hypoxic- ischemic encephalopathy may be followed by sudden deterioration, suggesting ongoing brain cell dysfunction, injury, and death; seizure intensity might increase.
  47. 47. Severe hypoxic-ischemic encephalopathy  Stupor or coma is typical. The infant may not respond to any physical stimulus.  Breathing may be irregular, and the infant often requires ventilatory support.  Generalized hypotonia and depressed deep tendon reflexes are common.  Neonatal reflexes (eg, sucking, swallowing, grasping, Moro) are absent.
  48. 48.  Disturbances of ocular motion. The pupils may be dilated, fixed, or poorly reactive to light  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 24-48 hours after onset, correlating with the phase of reperfusion injury
  49. 49.  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.  Irregularities of heart rate and blood pressure (BP) are common , as is death from cardiorespiratory failure.
  50. 50. Infants who survive severe hypoxic-ischemic encephalopathy  The level of alertness improves by days 4-5 of life.  Hypotonia and feeding difficulties persist, requiring tube feeding for weeks to months.
  51. 51. Multiorgan Dysfunction  Multiorgan systems involvement is a hallmark of hypoxic-ischemic encephalopathy.  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.
  52. 52.  Renal (46-72%) Renal failure presents as oliguria, leading to significant water and electrolyte imbalances.  Liver(80-85%) Elevated liver function test results, hyperammonemia, and coagulopathy can be seen. Necrotizing enterocolitis is rare
  53. 53.  Hematologic (32-54%) Disturbances include increased nucleated RBCs, neutropenia or neutrophilia, thrombocytopenia, and coagulopathy.
  54. 54. Neurologic Findings Cranial nerves  Lack of reflex activity mediated by the cranial nerves can indicate brainstem dysfunction.  Neurologic examination may be difficult in the small premature infant, but weakness of the lower extremities sometimes reflects the neuropathologic substrate of periventricular leukomalacia
  55. 55.  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.
  56. 56.  Patients with mild HIE often have mydriasis. Progression of the disease may produce miosis 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.
  57. 57.  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 or medullary reticular formation.  Ventilatory disturbances in HIE may manifest as periodic breathing apnea or just decreased respiratory drive.
  58. 58. Motorfunction  Begin the motor examination of an infant with suspected HIE by qualitatively and quantitatively observing his posture and spontaneous movements.  Specific patterns of motor weakness indicate cerebral injury patterns
  59. 59. Se iz ure s  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.  Tonic, unilateral, or focal seizures consistently have an EEG signature.  Subtle seizures may be a part of the HIE picture
  60. 60. Sarnat Staging System  The staging system proposed by Sarnat in 1976 is often useful in classifying the degree of encephalopathy.  Stages I, II, and III correlate with the descriptions of mild, moderate, and severe encephalopathy
  61. 61. Causes  Badawi et al investigated risk factors of neonatal encephalopathy in the Western Australian case control study.  Of the 164 infants with moderate-to-severe neonatal encephalopathy, preconceptual and antepartum risk factors were identified in 69% of cases;  24% of infants had a combination of antepartum and intrapartum risk factors,  whereas only 5% of infants had only intrapartum risk factors.  In this study, 5% had no identifiable risk factors.
  62. 62. Riskfactors forneonatal encephalopathy.
  63. 63. Laboratory Studies  There are nor specific tests to confirm or exclude a diagnosis of hypoxic-ischemic encephalopathy (HIE) because the diagnosis is made based on the history, physical and neurological examinations, and laboratory evidence  As always, the results of the tests should be interpreted in conjunction with the clinical history and the findings from physical examination.
  64. 64.  Serum electrolyte levels  In severe cases, daily assessment of serum electrolytes are valuable until the infant's status improves.  Markedly low serum sodium, potassium, and chloride levels in the presence of reduced urine flow and excessive weight gain may indicate acute tubular damage or syndrome of inappropriate antidiuretic hormone (SIADH) secretion, particularly during the initial 2-3 days of life.
  65. 65.  Renal function studies Serum creatinine levels, creatinine clearance, and BUN levels suffice in most cases.  Cardiac and liverenzymes These values are an adjunct to assess the degree of hypoxic-ischemic injury to these other organs.
  66. 66.  Coagulation system evaluation This includes prothrombin time, partial thromboplastin time, and fibrinogen levels.  ABG Blood gas monitoring is used to assess acid- base status and to avoid hyperoxia and hypoxia as well as hypercapnia and hypocapnia.
  67. 67. Medical Care  Following initial resuscitation and stabilization, treatment of (HIE) is largely supportive and should focus on adequate ventilation and perfusion,  careful fluid management,  avoidance of hypoglycemia and hyperglycemia and  treatment of seizures. Intervention strategies aim to avoid any further brain injury in these infants.
  68. 68. Supportive Care in Patients with Hypoxic-ischemic Encephalopathy  Most infants with severe hypoxic-ischemic encephalopathy need ventilatory support during first days of life.  Hypocapnia in particular may lead to severe brain hypoperfusion and cellular alkalosis and has been associated with worse neurodevelopmental outcomes.
  69. 69.  Of note, recent evidence indicates that increased FiO2 in the first 6 hours of life is a significant risk factor for adverse outcomes  Infants with hypoxic-ischemic encephalopathy are also at risk for pulmonary hypertension and should be monitored.
  70. 70. Perfusion and Blood Pressure Management  Studies indicate that a mean blood pressure (BP) above 35-40 mm Hg is necessary to avoid decreased cerebral perfusion.  Hypotension is common in infants with severe HIE and is due to myocardial dysfunction, capillary leak syndrome, and hypovolemia; hypotension should be promptly treated.  Dopamine or dobutamine can be used to achieve adequate cardiac output
  71. 71. Fluid and Electrolytes Management  Because of the concern for acute tubular necrosis (ATN) and syndrome of inappropriate antidiuretic hormone (SIADH) secretion, fluid restriction is typically recommended for these infants until renal function and urine output can be evaluated.
  72. 72.  However, fluid and electrolyte management must be individualized on the basis of clinical course, changes in weight, urine output, and the results of serum electrolyte and renal function studies.
  73. 73.  The role of prophylactic theophylline, given early after birth, in reducing renal dysfunction after HIE has been evaluated in 3 small randomized controlled trials  A single dose of theophylline (5-8 mg/kg) given within 1 hour of birth resulted in (1) decreased severe renal dysfunction (2) increased creatine clearance; (3) increased glomerular filtration rate (GFR); and (4) decreased b2 microglobulin excretion.
  74. 74.  Fluid and glucose homeostasis should be achieved.  Avoid hypoglycemia and hyperglycemia because both may accentuate brain damage  Hyperthermia management : Hyperthermia has been shown to be associated with increased risk of adverse outcomes in neonates with moderate-to- severe HIE
  75. 75. Treatment of Seizures  Hypoxic-ischemic encephalopathy is the most common cause of seizures in the neonatal period.  Seizures are generally self-limited to the first days of life  Current therapies include phenobarbital, phenytoin, and benzodiazepines
  76. 76. Hypothermia Therapy  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.
  77. 77.  Possible mechanisms include (1) reduced metabolic rate and energy depletion; (2) decreased excitatory transmitter release; (3) reduced alterations in ion flux; (4) reduced apoptosis due to HIE; and (5) reduced vascular permeability, edema, and disruptions of blood-brain barrier functions
  78. 78.  The clinical efficacy of therapeutic hypothermia in neonates with moderate-to- severe hypoxic-ischemic encephalopathy has been evaluated in 7 randomized controlled trials
  79. 79. Inclusion criteria))RCT  Near-term infants  Evidence of acute event around the time of birth - Apgar score of 5 or less at 10 minutes after birth  Evidence of moderate to severe encephalopathy at birth - Clinically determined
  80. 80. at least 2 of the following: lethargy, stupor, or coma; abnormal tone or posture; abnormal reflexes [suck, grasp, Moro, gag, stretch reflexes]; decreased or absent spontaneous activity; autonomic dysfunction [including bradycardia, abnormal pupils, apneas]; and clinical evidence of seizures, moderately or severely abnormal amplitude (aEEG)
  81. 81. Randomized controlled trials of therapeutic hypothermia formoderate-to-severe hypoxic-ischemic encephalopathy (HIE).
  82. 82. the results of the trials  No difference in composite outcome of death or severe disability were noted between the groups.  However, the study found that moderate hypothermia for 72 hours improved neurologic outcomes in survivors.  Surviving infants who were cooled were more likely to be free of neurologic abnormalities
  83. 83.  These clinical studies have been reassuring regarding safety and applicability of hypothermia therapy  Therapeutic hypothermia when applied within 6 hours of birth and maintained for 48-72 hours is a promising therapy for mild-to- moderate cases of HIE
  84. 84. hypothermia and its side effects  include coagulation defects,  leukocyte malfunctions,  pulmonary hypertension,  worsening of metabolic acidosis, and  abnormalities of cardiac rhythm, especially during rewarming.
  85. 85. What is the optimal timing of initiation of hypothermia therapy?  Cooling must begin early, within 6 hours of injury. However (the earlier the better )  Simplified method using widely available icepacks is an effective way to provide hypothermia therapy in referring centers while awaiting transfer to a tertiary NICU
  86. 86. 6hr???!!!>  On the other hand, a favorable outcome may be possible if the cooling begins beyond 6 hours after injury.  A current National Institute of Child Health and Human Development (NICHD) study is evaluating the efficacy of delayed hypothermia therapy for infants presenting at referral centers beyond 6 hours of life or with evolving encephalopathy.
  87. 87. What is the optimal duration of hypothermia therapy?  The greater the severity of the initial injury, the longer the duration of hypothermia needed for optimal neuroprotection.  The optimal duration of brain cooling in the human newborn has not been established
  88. 88. What is the best method?  Two methods have been used in clinical trials: selective head cooling and whole body cooling.
  89. 89. selective head cooling  In selective head cooling, a cap (CoolCap) with channels for circulating cold water is placed over the infant's head, and a pumping device facilitates continuous circulation of cold water.  Rectal temperature is then maintained at 34- 35°C for 72 hour
  90. 90. whole body hypothermia  In whole body hypothermia, the infant is placed on a commercially available cooling blanket, through which circulating cold water flows, so that the desired level of hypothermia is reached quickly and maintained for 72 hours.
  91. 91. What is the optimal rewarming method?  Rewarming is a critical period.  In clinical trials, rewarming was carried out gradually, over 6-8 hours.
  92. 92. Does hypothermia therapy result in long-termbenefits?  Several meta-analysis have been conducted and indicate that therapeutic hypothermia is beneficial to term newborns with hypoxic- ischemic encephalopathy
  93. 93. In a Cochrane review, Jacobs et al found that therapeutic hypothermia results in significant reduction in the following:  Combined outcome of mortality or major neurodevelopmental disability at age 18 months  Mortality  Neurodevelopmental disability in survivors
  94. 94.  They also found a significant increase in thrombocytopenia, although it was not clinically significant.  Benign sinus bradycardia
  95. 95.  Hypothermia therapy should be conducted under strict protocols and reserved to regional referral centers offering comprehensive multidisciplinary care and planning to conduct long-term neurodevelopmental follow-up.
  96. 96. NEUROPROTECTIVE STRATEGIES
  97. 97. Summary of potential neuroprotective strategies
  98. 98. Promising avenues include the following:  Prophylactic barbiturates: high-dose phenobarbital (40 mg/kg) was given over 1 hour to infants with severe hypoxic-ischemic encephalopathy.  Treated infants had fewer seizures  Treated infants also had fewer neurological deficits at age 3 years
  99. 99.  Erythropoietin: In a recent study, low-dose erythropoietin (300-500 U/kg) administered for 2 weeks starting in the first 48 hours of life decreased the incidence of death or moderate and severe disability at age 18 months  Subgroup analysis indicated that only infants with moderate disability benefited from this therapy.
  100. 100.  Allopurinol: Slight improvements in survival and cerebral blood flow (CBF) were noted in a small group of infants tested with this free- radical scavenger in one clinical trial.
  101. 101.  Excitatory amino acid (EAA) antagonists: (MK- 801, an EAA antagonist), has shown promising results in experimental animals and in a limited number of adult trials.  However, this drug has serious cardiovascular adverse effects
  102. 102. Medication Summary  Providing standard intensive care support, correcting metabolic acidosis, close monitoring of the fluid status, and seizure control are the main elements of treatment in patients with (HIE).  Anticonvulsants are the only specific drugs used often in this condition.
  103. 103. FurtherInpatient Care  Close physical therapy and developmental evaluations are needed prior to discharge in patients with (HIE).
  104. 104. References  Ferriero DM. Neonatal brain injury. NEng lJ Me d. Nov 4 2004;351(19):1985-95. [Medline].  Perlman JM. Brain injury in the term infant. Se m in Pe rinato l. Dec 2004;28(6):415-24. [Medline].  Grow J, Barks JD. Pathogenesis of hypoxic-ischemic cerebral injury in the term infant: current concepts.Clin Pe rinato l. Dec 2002;29(4):585-602, v. [Medline].  Srinivasakumar P, Zempel J, Wallendorf M, Lawrence R, Inder T, Mathur A. Therapeutic hypothermia in neonatal hypoxic ischemic encephalopathy: electrographic seizures and magnetic resonance imaging evidence of injury. JPe diatr. Aug 2013;163(2):465-70. [Medline].  Shankaran S. The postnatal management of the asphyxiated term infant. Clin Pe rinato l. Dec 2002;29(4):675-92. [Medline].  Stola A, Perlman J. Post-resuscitation strategies to avoid ongoing injury following intrapartum hypoxia-ischemia. Se m in Fe talNe o natalMe d. Dec 2008;13(6):424-31. [Medline].  Laptook A, Tyson J, Shankaran S, et al. Elevated temperature after hypoxic-ischemic encephalopathy: risk factor for adverse outcomes. Pe diatrics . Sep 2008;122(3):491- 9. [Medline]. [Full Text].  [Guideline] 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.  [Guideline] 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.Pe diatr. 1996;98:141-142. [Medline].
  105. 105. References  Papile LA, Rudolph AM, Heymann MA. Autoregulation of cerebral blood flow in the preterm fetal lamb.Pe dia tr Re s. Feb 1985;19(2):159-61. [Medline].  Rosenkrantz TS, Diana D, Munson J. Regulation of cerebral blood flow velocity in nonasphyxiated, very low birth weight infants with hyaline membrane disease. JPe rinato l. 1988;8(4):303-8. [Medline].  Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physio lRe v. Jan 2007;87(1):315-424. [Medline].  Roth SC, Baudin J, Cady E, Johal K, Townsend JP, Wyatt JS. Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years. De v Me d Child Ne uro l. Nov 1997;39(11):718-25. [Medline].  Berger R, Garnier Y. Pathophysiology of perinatal brain damage. Brain Re s Brain Re s Re v. Aug 1999;30(2):107- 34. [Medline].  Rivkin MJ. Hypoxic-ischemic brain injury in the term newborn. Neuropathology, clinical aspects, and neuroimaging. Clin Pe rinato l. Sep 1997;24(3):607-25. [Medline].  Vannucci RC. Mechanisms of perinatal hypoxic-ischemic brain damage. Se m in Pe rinato l. Oct 1993;17(5):330- 7. [Medline].  Vannucci RC, Yager JY, Vannucci SJ. Cerebral glucose and energy utilization during the evolution of hypoxic- ischemic brain damage in the immature rat. JCe re b Blo o d Flo w Me tab. Mar 1994;14(2):279-88.[Medline].  de Haan HH, Hasaart TH. Neuronal death after perinatal asphyxia. Eur JO bste t Gyne co lRe pro d Bio l. Aug 1995;61(2):123-7. [Medline].  McLean C, Ferriero D. Mechanisms of hypoxic-ischemic injury in the term infant. Se m in Pe rinato l. Dec 2004;28(6):425-32. [Medline].  Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates of the causes of death in children. Lance t. Mar 26-Apr 1 2005;365(9465):1147-
  106. 106. THANK YOU
  107. 107. Case presentation  A male , post term (42)W , NVD, AGA , BW 3.625, admitted to our NICU at 12:15 am with a diagnosis of HIE.  The mother is a 34yr old multipara G3 P2 A1,low socioeonomic status and suferred from raised blood pressure and UTI during the last trimester for which she received oral therapy .  Iron deficieny anaemia started during 2nd trimester and 3rd for which she received oral iron tab
  108. 108. Natal History  Spontaneous vaginal delivery , spont. Rupture of memb.,clear amnion , vertex presentation , fetal monitoring : absent +ve data.  APGAR score 1st min is 1 and immediat resuscitation started in the delivery room , drying ,warming , positioning and AMBU bag vetilation .  5 min and 10 min apgar was 5 , intubation and transfere to NICU
  109. 109. ABG cord blood result:  PH 6.8  Pco2 : 72  Po2 : 27  Hco3  BE -14
  110. 110.  Whole body cooling was started at 12:30 am (within 15 min of birth)  Monitoring of pulse, temp, bl press and ECG cardiac monitor and other aspect of incubator care were started prompetly  IV fluid , broad spectrum antibiotic and complete panil of initial investigations including CBC , electrolyte , pt, ptt, liver enz , BUN and creatinin together with CK and LDH
  111. 111. COOLING for 72hr  On D 2 : prolonged PT 50 sec and PTT 2 min for which plasma trnsfusion was given  Erythropoietin inj. are Started (neuroprotection)  Convulsion occured , generalized colonic , phenobarbiton inj was given (loading and maintenance)  D3: convulsions un controlled , add Epanutin  D4: Gradual rewarming was started
  112. 112.  D5: significant apnea attacks , PTV was given then NCPAP ( peep 5 , fio2 30%)  Hypoactive , poor reflexes  BP monitoring showed rising MAP :88 , 72, 90.
  113. 113.  D7: nasal pronge ( stop NCPAP)  Full fontanelle: CSF analysis (bloody tap)  Cr U/S : free  MRI : pic. Of cerebral oedema and hypoxic changes  Reduced total fluid intake with gradual introduction of NG feeding
  114. 114.  D8: ECG monitor multiple premature ventricular contractions associated with generalized tonic convulsions treated with IV lidocaine  D11 : Off o2  D24: stable , transfered to bed , nasogastric full feeding , stop IV fluid and antibiotics  Convulsions controlled , maintenance sominaletta and epanutin orally  Oral Topiramate
  115. 115. Discharge plan:  Educate the parent about NG feeding with gradual stimulation of oral suckling ( pacifiers)  Follow up at Neonatal outpt clinic and blood pressure management  Gradual withdrawal of anti convulsant under supervision of ped. Neurology clinic  F/u of MRI after 3 month of discharge  Cont. care and support in pediat outpt clinic
  116. 116.  Fundus exam and hearing assessment to exclude potential handicap  Follow up of developmental mile stones

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