This document discusses hypoxic ischemic encephalopathy (HIE), including its pathophysiology, management, and prognostic factors. HIE is caused by inadequate oxygen and blood flow to the brain, commonly due to perinatal asphyxia. Standard management includes therapeutic hypothermia to reduce brain injury. Predictors of outcome include clinical exam findings, amplitude integrated EEG patterns within 72 hours, and MRI findings such as basal ganglia injury. New treatments under investigation include xenon gas, erythropiotine, and melatonin for their neuroprotective properties, as well as stem cell transplantation. Prognosis depends on injury severity and gestational age, with term infants generally having a better outlook than preterm infants.

1. Hypoxic Ischemic
Encephalopathy (HIE)
SABER JAN (PGY -2 PEDIATRIC NEUROLOGY)
CHIEF’S ROUND
FEB 9, 2018

2. Objectives
- What is HIE?
- What is the pathophysiology of HIE?
- What are the predictive values of clinical exam, aEEG, cEEG, MRI, EP?
- Do we over cool or under cool babies?
- What is new management?

3. Case scenario
Maternal history is unremarkable.
Pregnancy: routine follow up, normal US, protective serology
Delivery: placental abruption, fetal bradycardia.
GA : 40+5 weeks
Urgent CS
APGAR 4/6/9

4. Case scenario
Resuscitation: HR>100, PPV >CPAP, had increased WOB
Birth weight (kg): 2.8 kg
Cord gas UA: 6.96/---/109/23/-14
Cord gas UV: 7.14/---/62/20/-10.6
Clinical progression: noted to have irritability, hypertonia. Good sucking, gag, palmer grasp,
and partial moro, presence of DTR. No seizures.

5. To cool or not to cool?
Any predictive test to help pre-
cooling/cooling/ post cooling?
What do you tell family?

6. Introduction
- Most common cause of cerebral palsy (CP) and other severe neurological deficits in children.
- 1.5/1000 live births
- Inadequate blood flow and oxygen supply to the brain resulting in focal or diffuse brain injury

7. Etiology
- Perinatal asphyxia (most important) in utero or postnatally.
- Intrauterine asphyxia: secondary to inadequate placental perfusion
A- fetal factors (fetal bradycardia, fetal thrombosis, and fetal hemorrhage),
B- maternal factors (preeclampsia, abruptio-placentae, maternal hypotension, severe anemia,
asthma and chronic vascular disease), or tight nuchal cord
C- cord prolapse.
- Postnatal asphyxia : secondary to pulmonary failure such as severe hyaline membrane disease,
meconium aspiration syndrome, pneumonia, or congenital cardiac disease

8. Pathogenesis
- Asphyxia is leading to brain ischemia (reduced cerebral blood flow) and hypoxia (reduced
cerebral oxygen).
- Hypoperfusion, in conjunction with hypoxia, leads to a cascade of events including acidosis,
release of inflammatory mediators and free radical formation.
- The result is loss of normal cerebral autoregulation and diffuse brain injury
- The exact nature of the injury depends on the severity and duration of hypoxia and degree of
brain maturation. In term infants, myelinated fibers are more metabolically active and hence
more vulnerable to HIE

9. Pathogenesis

10. Hypothermia
- Standard of care
- Proven evidence of lower morbidity and mortality
- Rectal temperature of 34±0.5°C
- Duration: 72hr

11. Cooling Criteria
Infants ≥36 weeks’ gestation with HIE who are ≤6 h of age and who meet both treatment criteria A and B:
Criteria A
Any two of the following:
- Apgar score <5 at 10 min of age.
- Continued need for ventilation and resuscitation at 10 min of age.
- Metabolic acidosis with pH <7 or base deficit >16 mmol/L in cord or arterial blood gases measured within
1 h of birth.
AND
Criteria B
Moderate (Sarnat stage II) or severe (Sarnat stage III) encephalopathy demonstrated by the presence of
seizures or at least one sign in at least three of the six categories shown in the next table.

12. Clinical Manifestation

13. Clinical Manifestation

14. Cooling Criteria
All Infants who fulfill criteria A should then undergo a careful neurological examination to
determine whether they fulfill criteria B.
- If possible, it is helpful to assess infants with an aEEG for at least 20 min before 5.5 h of age to
document abnormal tracings or seizures

15. Complications of Cooling
- Mild hypothermia is safe with no serious side effects reported
- Mild bradycardia
- Mild hypotension
- Arrhythmias,
- Thrombocytopenia
- Scleroderma/edema have been described

16. Predictive tests
Pre cooling cooling Post cooling
Clinical Exam
aEEG
aEEG
cEEG
MRI
6hr
72hr

17. What is the
predictive value
of clinic exam?

18. The predictive value of clinical
examination in non cooled HIE babies
Change overtime ( day 1, 2, 3, and time of discharge).
Examination at all time
point s correlated significantly with neurological outcome
at 24 months.
The best correlations were
found to be (1) neurological examinati on at discharge
(r=0.65, p<0.001), (2) Sarnat grading (r=0.64,
p<0.001), and (3) ATNAT on day 3 (r=0.46, p<0.001).
The best predictive value was seen with neuro-
logical examination at discharge (positive and negative
predictive values of 86% and 72% respec-
tively).

19. To evaluate whether therapeutic hypothermia alters the prognostic value of clinical grading of neonatal
encephalopathy
Multicenter study of 234 term infants
Treatment did not significantly affect HIE grade at day 4 (P 0.17, analysis of covariance), adjusted for the
effect of pre-randomization HIE grade (P .001).
Infants with moderate encephalopathy post cooling have mixed outcome ( good vs poor)
Infants with moderate encephalopathy on day 4 may have a more favorable prognosis after hypothermia
treatment than expected after standard care

20. The value of clinical exam in inclusion
criteria
- Mild HIE is a major exclusion criteria in many studies (can reach up to >50% of the excluded HIE
babies)
- Limited evidence for cooling mild HIE

21. Different institute experiences in
cooling non eligible HIE babies
- A total of 207 infants received TH, 104 (50%) did not meet
the eligibility criteria defined in NSW policy directive.
- Seventy percent of infants (73 out of 104) not meeting
eligibility criteria did not fulfil the criteria for ‘evidence of
asphyxia’, although half of them met ‘moderate or severe
encephalopathy criterion’
- Majority didn’t continue the cooling period

22. - Significant variability in practice exists when caring for
infants with HIE who do not meet standard inclusion criteria
- Scenarios with the most variability included HIE in a late
preterm infant and HIE following a postnatal code.
- Provision of therapeutic hypothermia outside of standard
guidelines was not influenced by number of years in practice,
neonatal intensive care type (NICU) or NICU size.

23. What about our
experience?

24. Predictive value of aEEG
- High positive (PPV) and negative predictive values (NPV) during the first hours of life in
normothermic infants
- Look for normalization of the background pattern (BP) and emergence of sleep-wake cycling
(SWC).

25. Predictive value of aEEG (pre-cooling era)
Toet MC, Hellström-Westas L, Groenendaal F, Eken P, de Vries LS: Amplitude
integrated EEG 3 and 6 hours after birth in full term neonates with hypoxic-
ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed 1999; 81:F19–F23.
Flat tracing (FT): Very low voltage, mainly inactive
(isoelectric) tracing with activity below 5 µV.
Continuous extremely low voltage (CLV): Continuous
background pattern of very low voltage (around or
below 5µV).
Burst–suppression (BS): Discontinuous background
pattern; periods of very low voltage (inactivity)
intermixed with burst of higher amplitude.
Discontinuous normal voltage (DNV): Discontinuous
trace, where the voltage is predominantly above 5µV.
Continuous normal voltage (CNV): Continuous activity
with voltage 10–25 (–50) µV. Epileptic activity was also
identified.

26. Predictive value of aEEG (pre-cooling era)
Outcome: CP, death
Follow up: ~ 12 months

27. Predictive value of aEEG (post-cooling era)
- Cooling can lower the predictive value of
aEEG
- Data from TOBY trial:
- aEEG was recorded for at least 30 min
within 6 h of birth prior to randomization
- However, the difference is not statically
significant, but consistent with many
observational trials.
Azzopardi, D. (2013). Predictive value of the amplitude
integrated EEG in infants with hypoxic ischaemic
encephalopathy: data from a randomised trial of therapeutic
hypothermia. Archives of Disease in Childhood - Fetal and
Neonatal Edition, 99(1).

28. Predictive value of aEEG (post-cooling era)

29. Predictive value of aEEG (post-cooling era)
Early aEEG patterns can be used to predict outcome for infants treated with normothermia but
not hypothermia.
Infants with good outcome had normalized background pattern by 24 hours when treated with
normothermia and by 48 hours when treated with hypothermia
Thoresen M, Hellstro¨m-Westas L, Liu X, de Vries LS. Effect of hypothermia on amplitude-integrated
electroencephalogram in infants with asphyxia. Pediatrics 2010; 126(1): e131–9

30. Predictive value of aEEG
- Systematic review was published in 2016
- This study confirms that aEEG´s background
activity, as recorded during the first 72 hours
after birth, has a strong predictive value in
infants with HIE treated or not with TH.
- Predictive values of traces throughout the
following 72 hours are a helpful guide when
considering and counselling parents about the
foreseeable long-term neurological outcome

31. Predictive value of cEEG
- Not commonly used as a routine.
- Mainly used if there a suspicion of seizures.
- Better diagnostic tool for seizures: Higher sensitivity and specificity than aEEG for seizure
detection.
- Limited data for the predictive value compared to aEEG

32. Predictive value of cEEG
- Many studies recommended its use as part of routine
cooling protocol instead of aEEG.
- It provides prognostic information about early MRI
outcome and accurately identifies electrographic seizures,
nearly half of which are subclinical.

33. Predictive value of MRI
- Injury to the basal ganglia/thalami is highly predictive of major neuro-motor and cognitive
problems.
- Correlate with 12- to 24-month neurodevelopmental outcomes. However, MRI is not useful
until 24 h after birth, unless diffusion-weighted imaging or MR spectroscopy is part of the
imaging protocol.

34. Sample size: 173 babies.
The basal ganglia/thalamus pattern was associated with more severe neonatal signs,
including more intensive resuscitation at birth (P = .001), more severe encephalopathy (P =
.0001), and more severe seizures (P = .0001). The basal ganglia/thalamus pattern was
associated with the most impaired motor and cognitive outcome at 30 months.

35. MRI imaging
- MRI is the most sensitive and specific imaging modality for evaluating suspected neonatal HIE
- DWI demonstrate cytotoxic edema in acute phase (10-12 days) before the signal intensity
changes are evident on conventional T1- or T2-weighted images.
- Limitation of DWI: false negative result in the first 24hr.
- MRS: first 24 h after birth in a full-term neonate is very sensitive to the severity of HIE brain
injury and can predict adverse outcome.
- Elevated lactate/creatine ratio on day 1 of life is a predictor of adverse neurological outcome
- Decreased N-acetylaspartate (NAA), increased choline and glutamine-glutamate peaks are also
seen in neonatal HIE.

36. Pattern of Injury : Full-term
In term neonates, mild to
moderate HI injury produces
parasagittal watershed zone
infarcts between
anterior/MCA and
middle/posterior cerebral
artery. Both the cortex and
underlying subcortical white
matter are involved

37. Severe HIE in term
Injury to metabolically active tissues such as ventrolateral thalami, posterior putamina, hippocampi,
brainstem, corticospinal tracts, and sensorimotor cortex.
BG injury is more common than parasagittal pattern and carries the worst prognosis

38. What about MRI with no or minor
degree of injury post TH?
- Limited long term studies
- A cohort study by Rollins et.al. 2014 (1): found lower scores were associated with fewer motor and
tone problems but a normal MRI did not consistently equate to normal cognitive and language
measures around 24 months of age.
- Follow up : 24 months,
- sample size : 62 infants.
- Mild degrees of brain injury may be associated with developmental disabilities in early childhood
- Careful when counseling families
(1) Rollins, N., Booth, T., Morriss, M. C., Sanchez, P., Heyne, R., & Chalak, L. (2014). Predictive Value of Neonatal
MRI Showing No or Minor Degrees of Brain Injury After Hypothermia. Pediatric Neurology, 50(5), 447-451

39. Predictive value of EP (VEP/SEP)
- Limited number of studies
Systematic review by van Laerhoven et.al (2012) (5
studies)
The prognostic value of SEP and VEP is promising but
should be investigated in well-designed prospective
studies before standardized clinical use is advocated

40. Predictive value of EP (VEP/SEP)
- Cooling alters the prognostic value of
neurophysiologic tests in neonates with
moderate or severe HIE.
- SEPs should be interpreted with caution
in this population and need to be re-
evaluated in larger studies

41. Management
- Systematic support: Respiratory and Cardiovascular support
- Fluid, electrolytes, nutrition
- Seizure management
- Hypothermia

42. What’s new in management?
- Xenon
• Gas, used as an inhaled anasthetic
• Neuroprotective qualities, such as affecting other ion channels and reducing neurotransmitter release in
general.
• Easily crosses the BBB, takes rapid effect,
• Can be rapidly withdrawn
• Myocardial protective properties with very limited potential cardiovascular effects
• Passed phase 1 trial, ongoing phase 2

43. What’s new in management?
- Erythropiotine
• Neuroprotection against apoptosis and anti-inflammatory effect
• Ongoing trials, not approved yet.
- Melatonin
• Free radical scavenger of the hydroxyl radical, oxygen, and hydrogen peroxide.
• Anti-inflammatory effect

44. What’s new in management?
- Stem cell transplant:
• May increase levels of brain trophic factors and anti-apoptotic factors,
• Decrease inflammation,
• Preserve endogenous tissue,
• Support replacement of damaged cell
• Autologous umbilical cord blood (UCB)
• One open label trial
• Randomized double blinded trials are needed

45. Prognosis
- Depends on the severity of injury and gestational age of the infant.
- Poor outcome with:
• Poor neurological exam.
• Severe EEG abnormalities within 72 hr of life.
• Cortex and BG involvement
• Increase lactate on MRS within 24 h of life
-Term infants with mild encephalopathy generally have good prognosis and show complete
recovery; however, 20% of infants may die in the neonatal period and another 25% may develop
significant neurological deficit.

46. References
- Bano, S., Chaudhary, V., & Garga, U. (2017). Neonatal hypoxic-ischemic encephalopathy: A
radiological review. Journal of Pediatric Neurosciences, 12(1), 1. doi:10.4103/1817-1745.205646
- Douglas-Escobar, M., & Weiss, M. D. (2015). Hypoxic-Ischemic Encephalopathy. JAMA
Pediatrics, 169(4), 397. doi:10.1001/jamapediatrics.2014.3269
- Cotten, C. M., Murtha, A. P., Goldberg, R. N., Grotegut, C. A., Smith, P. B., Goldstein, R. F., . . .
Kurtzberg, J. (2014). Feasibility of Autologous Cord Blood Cells for Infants with Hypoxic-Ischemic
Encephalopathy. The Journal of Pediatrics, 164(5). doi:10.1016/j.jpeds.2013.11.036

47. Special thanks to Dr. McNamara