Hypoxic Ischemic Encephalopathy

1. Hypoxic
Ischaemic
Encephalopathy
Dr.Pankaj Bajaj
2nd year DNB
DEPT. OF PEDIATRICS
J.L.N. HOSPITAL & RESEARCH CENTRE, BHILAI

2. Overview
• Background
• Definition
• Etiology
• Pathophysiology
• Clinical features
• Diagnosis
• Treatment.

3. Background
• 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.
• Hypoxic-ischemic encephalopathy is characterized by clinical and
laboratory evidence of acute or subacute brain injury due to asphyxia
(ie, hypoxia, acidosis). Most often, the exact timing and underlying
cause remain unknown.

4. Definition
• Anoxia
is a term used to indicate the consequences of complete lack of oxygen as a
result of a number of primary causes
• Hypoxia
refers to an arterial concentration of oxygen that is less than normal
• Ischemia
refers to blood flow to cells or organs that is insufficient to maintain their
normal function
Biagioni E, Mercuri E, Rutherford M, et al: Combined use of electroencephalogram and magnetic
resonance imaging in full-term neonates with acute encephalopathy. Pediatrics 2001;107:461

5. • Hypoxic-ischemic encephalopathy
Is an abnormal neurobehavioral state in which the predominant pathogenic
mechanism is impaired cerebral blood flow that may result in neonatal
death or be manifested later as cerebral palsy or mental deficiency.
1996 guidelines from the AAP and ACOG for hypoxic-ischemic encephalopathy
(HIE)
• 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
Nelson Textbook of Pediatrics 19th ed.2010 . pages 566 - 568

6. Epidimiology
• Frequency
a) Birth asphyxia is the cause of 23% of all neonatal deaths worldwide.
b) It is one of the top 20 leading causes of burden of disease in all age
groups by the World Health Organization.
c) It is the fifth largest cause of death of children younger than 5 years (8%)
d) More than a million children who survive birth asphyxia develop
problems such as cerebral palsy, mental retardation, learning
difficulties, and other disabilities.
Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates of the causes of death in
children. Lancet. Mar 26-Apr 1 2005;365(9465):1147-52.

7. • Mortality/Morbidity:
a) In severe hypoxic-ischemic encephalopathy, the mortality rate is
reportedly 25-50%.
b) As many as 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.
c) The infants who survive moderately severe hypoxic-ischemic
encephalopathy, 30-50% may have serious long-term complications, and
10-20% have minor neurological morbidities.
d) Infants with mild hypoxic-ischemic encephalopathy tend to be free from
serious CNS complications.
Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic
hypothermia after neonatal encephalopathy: multicenter randomised trial. Lancet.
2005;365:663-70.

8. • Race
No predilection is noted.
• Sex
No predilection is observed.
• Age
Most often, the condition is noted in infants who are term at birth.
van Handel M, Swaab H, de Vries LS, Jongmans MJ. Long-term cognitive and
behavioral consequences of neonatal encephalopathy following perinatal asphyxia: a
review. Eur J Pediatr. Jul 2007;166(7):645-54

9. Risk factors
Preconceptual
• IDDM
• Thyroid disease
• Fertility treatments
• Nulliparity
• Advanced maternal
age.
Antepartum
• Severe pre-
eclampsia
• Placental abruption
• IUGR
• Antepartum
haemorrhage
Intrapartum
• Breech
• Cord prolapse
• Stat C-section
• Induction
• Maternal pyrexia

10. Pathophysiology
Decreased bood
flow to placenta
Decreased oxygen delivery to
the foetus.
Increased oxygen
consumption in
mother and foetus.

11. Pathophysiology (contd)
• Brief asphyxia
• Prolong asphyxia
• Anaerobic metabolism.

12. 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.

13. 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. After transient
recovery of cerebral energy
metabolism, a secondary
phase of apoptotic neuronal
death occurs. ROS = Reactive
oxygen species.

14. Clinical features- Sarnat Staging System
Stage 1 Stage 2 Stage 3
Level of
conciousness
Hyperalert Lethargic/obtunded Stuporous
Neuromuscular control
Muscle tone Normal Mild hypotonia Flaccid
Posture Mild distal flexion Strong distal flexion Intermittent
decerebration
Stretch reflex Overactive Overactive Decreased/absent
Segmental
myoclonus
Present Present Absent
Complex Reflexes
Suck Weak Weak/absent Absent
Moro Strong, low
threshold
Weak; incomplete,
high threshold
Absent
Oculovestibular Normal Overactive Weak/absent
Tonic neck Slight Strong Absent

15. Autonomic
function
Generalised
sympathetic
Generalised
parasympathetic
Both systems
depressed
Pupils Mydriasis Miosis Variable;ofetn
unequal;poor light
reflex
Heart rate Tachycardia Bradycardia Variable
Bronchial &
salivary secretions
Sparse Profuse Variable
GI motility Normal/decreased Increased,diarrhea Variable
Seizures None Common; focal /
multifocal
Uncommon
EEG Normal Early : low voltage
continuous delta &
theta.
Later: periodic
pattern
Seizures: focal 1 Hz
spike and wave
Early: periodic with
isopotential phases.
Later: totally
isopotential
Duration 1-3 days 2-14 days Hours . weeks

16. Diagnosis
• 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.
• Laboratory studies include :-
Study
Serum electrolyte 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 (SIADH) secretion,
particularly during the initial 2-3 days of life.
Renal function Serum creatinine levels, creatinine clearance, and BUN levels
Cardiac & liver enzymes Assess the degree of hypoxic-ischemic injury to other organs
Coagulation system Prothrombin time, partial thromboplastin time, and fibrinogen
levels.
ABG Assess acid-base status and to avoid hyperoxia and hypoxia as
well as hypercapnia and hypocapnia.

17. Imaging studies:-
Cranial US:
a) Convenient, noninvasive, relatively low-cost
and non –radiation screening examination
of the hemodynamically unstable neonate
at the bedside.
b) Doppler study and resistive index (RI)
provide additional information on cerebral
perfusion.
c) RI decreases with increasing gestational
age, and thus correlation with gestational
age is necessary for accurate interpretation
of RI results.
d) Decreased RI is abnormal & is postulated to
be caused by impairment in cerebral
autoregulation.
e) Sustained asphyxia & ICH or diffuse cerebral
edema results in increased RI and is
indicative of a poor outcome.
PV-cysts (swiss cheese
appearance)

18. Cranial CT:
a) CT technology provides a
rapid mode of screening for
ICH & hydrocephalus in a sick
neonate without the need for
sedation.
b) CT is the least sensitive
modality for evaluation of HIE
because of poor parenchymal
contrast resolution due to:
 high water content in the
neonatal brain.
 high protein content of the
cerebrospinal fluid, which
result in.
 CT has the inherent
disadvantage of radiation
exposure.
Unenhanced CT scan shows diffuse cortical swelling
and hypoattenuation in the white matter relative to
areas of preserved cortex, A small amount of
extraaxial hemorrhage adjacent to the left frontal
lobe is also seen (arrow).

19. Cranial MRI
a) The most sensitive and
specific imaging technique
for examining infants with
suspected hypoxic-
ischemic brain injury.
b) Hypoxic-ischemic injury
(deep grey
matter,cortex)demonstrat
es characteristic T1
hyperintensity and
variable T2 intensity.
c) Ischemic injury generally
results in T1 hypointensity
&T2 hyperintensity (white
matter)due to ischemia-
induced edema.
relatively subtle increases in signal intensity in the perirolandic
regions, posterior aspect of the putamen, lateral aspects of the
thalamus, and corpus callosum.
Bottom: show diffuse abnormally high signal intensity in the
supratentorial parenchyma in comparison with the superior
aspect of the cerebellum, which has normal signal intensity.

20. Histological findings
Bilateral acute infarctions of the frontal lobe are shown.
The infarctions depicted in the figure (arrows) are
consistent with watershed infarctions secondary to global
hypoperfusion.
presence of pyknotic and hyperchromatic
nuclei, the loss of cytoplasmic Nissl
substance, and neuronal shrinkage and
angulation (arrow). These alterations begin to
appear approximately 6 hours following hypoxic-
ischemic insult.

21. Reactive astrocytosis is evident approximately
24-48 hours after the primary hypoxic-ischemic
event.
Periventricular leukomalacia is depicted.
Note the extensive hemorrhage within the cystic space as well
as the hemosiderin-laden macrophages around the lesional
rim.

22. Other studies
Amplitude-integrated electroencephalography (aEEG)
a) The abnormalities seen in infants with moderate-to-severe hypoxic-
ischemic encephalopathy include the following:
b) Discontinuous tracing characterized by a lower margin below 5 mV and
an upper margin above 10 mV
c) Burst suppression pattern characterized by a background with minimum
amplitude (0-2 mV) without variability and occasional high voltage bursts
(>25 mV)
d) Continuous low voltage pattern characterized by a continuous low
voltage background (< 5 mV)
e) Inactive pattern with no detectable cortical activity
f) Seizures, usually seen as an abrupt rise in both the lower and upper
margin

23. Standard EEG
Generalized depression of the background rhythm and
voltage, with varying degrees of superimposed seizures, are
early findings. EEG characteristics associated with abnormal
outcomes include
a) background amplitude of less than 30 mV.
b) interburst interval of more than 30 seconds.
c) electrographic seizures.
d) absence of sleep-wake cycle at 48 hours.

24. Treatment
Medical care
a) Initial Resuscitation and Stabilization-
• Delivery room management follows standard Neonatal Resuscitation
Program (NRP) guidelines. Close attention should be paid to appropriate
oxygen delivery, perfusion status, and avoidance of hypoglycemia and
hyperthermia.
• A lot of attention is currently focused on resuscitation with room air
versus 100% oxygen in the delivery room. Several clinical trials indicate
that room air resuscitation for infants with perinatal asphyxia is as
effective as resuscitation with 100% oxygen.
• International Liaison Committee on Resuscitation (ILCOR)
recommendations include initiating neonatal resuscitation with
concentrations of oxygen between 21-100%
Guideline] Ten VS, Matsiukevich D. Room air or 100% oxygen for
resuscitation of infants with perinatal depression. Curr Opin Pediatr. Apr
2009;21(2):188-93

25. b) Supportive Care in Patients with Hypoxic-ischemic
Encephalopathy
• Most infants with severe hypoxic-ischemic encephalopathy need
ventilatory support during first days of life.
• The role of mechanical ventilation is to maintain the blood gases and
acid-base status in the physiological ranges and prevent
hypoxia, hyperoxia, hypercapnia, and hypocapnia.
• Infants with hypoxic-ischemic encephalopathy are also at risk for
pulmonary hypertension and should be monitored. Nitric oxide (NO) may
be used according to published guidelines.
[Guideline] American Academy of Pediatrics. Committee on Fetus and Newborn. Use of
inhaled nitric oxide. Pediatrics. Aug 2000;106(2 Pt 1):344-5.

26. c) Perfusion and Blood Pressure Management
• A mean blood pressure (BP) above 35-40 mm Hg is necessary to avoid
decreased cerebral perfusion.
• Hypotension is common in infants with severe hypoxic-ischemic
encephalopathy 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 in these patients. Avoiding iatrogenic hypertensive episodes is also
important.

27. d) Fluid and Electrolytes Management
• Prophylactic theophylline, given early after birth helps in reducing renal
dysfunction
• A single dose of theophylline (5-8 mg/kg) given within 1 hour of birth resulted in
(1) decreased severe renal dysfunction (defined as creatinine level >1.5 mg/dL for 2
consecutive days);
(2) increased creatine clearance;
(3) increased glomerular filtration rate (GFR); and
(4) decreased b2 microglobulin excretion.
• Avoid hypoglycemia and hyperglycemia because both may accentuate brain
damage.
Jenik AG, Ceriani Cernadas JM, Gorenstein A, et al. A randomized, double-blind, placebo-controlled trial of
the effects of prophylactic theophylline on renal function in term neonates with perinatal
asphyxia.Pediatrics. 2000;105:E45

28. e) Treatment of Seizures
• Hypoxic-ischemic encephalopathy is the most common cause of seizures
in the neonatal period.
• Current therapies available to treat neonates with seizures include
phenobarbital, phenytoin, and benzodiazepines.
• Phenobarbital has been shown to be effective in only 29-50% of cases,
• Phenytoin only offers an additional 15% efficacy.
• Benzodiazepines, particularly lorazepam, may offer some additional
efficacy
Boylan GB, Rennie JM, Chorley G, et al. Second-line anticonvulsant treatment of neonatal
seizures: a video-EEG monitoring study. Neurology. Feb 10 2004;62(3):486-8.

29. g) Medication summary
Phenobarbital
(20mg/kg I V)
Phenytoin
(20mg/kg)
Lorazepam
(0.1mg/kg)
Anti
convulsants
Dopamine
dobutamine
Cardiovascular
agents

30. f) Hypothermia Therapy
• Mild hypothermia (3-4°C below baseline temperature) applied within a few hours
(no later than 6 h) of injury is neuroprotective. 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 hypoxic-ischemic encephalopathy; and
(5) reduced vascular permeability, edema, and disruptions of blood-brain barrier
functions.
• 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 hypoxic-ischemic
encephalopathy.
Best Evidence] Azzopardi DV, Strohm B, Edwards AD, et al. Moderate hypothermia to treat
perinatal asphyxial encephalopathy. N Engl J Med. Oct 1 2009;361(14):1349-58.

31. h) Diet
• In most cases, the infant is restricted to nothing by mouth (NPO) during
the first 3 days of life or until the general level of alertness and
consciousness improves.
• In addition, infants undergoing hypothermia therapy should remain NPO
until rewarmed. Enteral feeds should be carefully initiated and the use of
trophic feeds is initially advisable (about 5 mL every 3-4 h).
• Infants should be monitored carefully for signs and symptoms of
necrotizing enterocolitis, for which infants with perinatal asphyxia are at
high risk.

32. i) potential neuroprotective strategies.

33. Surgical care
• In cases of posterior cranial fossa hematoma, surgical
drainage may be lifesaving if no additional pathologies are
present.
Further Inpatient Care
• Close physical therapy and developmental evaluations are
needed prior to discharge in patients with hypoxic-ischemic
encephalopathy (HIE).

34. Further Outpatient Care
• The goal of follow-up is to detect impairments and promote early
intervention for those infants who require it.
• Growth parameters including head circumference should be closely
monitored in all infants with hypoxic-ischemic encephalopathy.
• In infants diagnosed with moderate-to-severe hypoxic-ischemic
encephalopathy with either abnormal neurologic examination findings or
feeding difficulties, intensive follow-up is recommended. include follow-up
by developmental pediatrician and pediatric neurologic.
• In infants with moderate hypoxic-ischemic encephalopathy but no feeding
difficulties and normal neurologic examination findings, routine care is
appropriate.

35. Prognosis
• Lack of spontaneous respiratory effort within 20-30 minutes of birth is
almost always associated with death.
• The presence of seizures is an ominous sign.
• Abnormal clinical neurological findings persisting beyond the first 7-10
days of life usually indicate poor prognosis.
• EEG at about 7 days that reveals normal background activity is a good
prognostic sign.
• Persistent feeding difficulties, which generally are due to abnormal tone of
the muscles of sucking and swallowing, also suggest significant CNS
damage.
• Poor head growth during the postnatal period and the first year of life is a
sensitive finding predicting higher frequency of neurologic deficits.
Patel J, Edwards AD. Prediction of outcome after perinatal asphyxia. Curr Opin Pediatr. Apr
1997;9(2):128-32.