1) Therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy has been shown to reduce mortality and morbidity when initiated before 6 hours of life. 2) Studies have found hypothermia reduces brain injury as seen on MRI and lowers rates of cerebral palsy, cognitive impairment, and death when compared to normothermia. 3) While mid-term outcomes up to age 7 show benefits of hypothermia, long-term follow up is still needed to fully understand impacts on neurocognitive, behavioral, and social development into childhood. Combining hypothermia with neuroprotective drugs is a promising area for further research.

1. Therapeutic hypothermia for
neonatal hypoxic-ischemic
encephalopathy
Olivier BAUD
Réanimation et Pédiatrie Néonatales
INSERM U676
DHU PROTECT
Hôpital Robert Debré, APHP
International Neonatology Conference Kiev 6th March 2013

2. HIE in the world
Major public health issue
23% of the total 4 M deaths in the world
20% of global incidence of cerebral palsy
1.44 million
0.94 million
1.1 million
Lawn JE et al, Lancet 2005

3. Etiologies of HIE
Maternal Fetal
Cardiac arrest Fetomaternal haemorrhage
Asphyxiation Twin to twin transfusion
Severe anaphylaxis Severe iso-immune haemolytic disease
Status epilepticus Cardiac arrhythmia
Hypovolemic shock
Uteroplacental
Placental abruption
Cord prolapse
Uterine rupture
Hyperstimulation with oxytocic
agents

4. HIE severity and morbidity/mortality
Moderately severe Severe
1-3 / 1000 livebirths 0.5-2 / 1000 livebirths
Neonatal mortality: 50-75%
Severe handicaps: 30-50% (epilepsy, Severe handicaps: 80%
cognitive impairment, CP…) ccccc
Mild handicaps: 10-20% Mild handicaps: 10-20%
Normal outcome at 2y: 30-40% Normal outcome at 2y: 10%

5. Sarnat & Sarnat staging (1976)
Stage 1 Stage 2 Stage 3
Consciousness hyperalert Lethargic of obtunded Stupor or coma
Activity Normal Decreased Absent
Neuromuscular control
Muscle tone Normal Mild hypotonia Flaccid
Posture Mild distal flexion Strong distal flexion Intermittent decerebration
Strech reflexes
Overactive Overactive Decreased or absent
Primitive reflexes
Suck Weak Weak or absent Absent
Moro Strong Weak, incomplete Absent
Tonic neck
Slight Strong Absent
Autonomic function
Pupils Normal Miosis Mydriase or variable, unequal
Heart rate Tachycardia Bradycardia Variable
Seizures None Common Uncommon
Stage 0 = Normal

6. Early evaluation of HIE
• Early and repeated clinical examination: Classification de Sarnat et Sarnat
staging+++
• Clinical investigations:
- EEG: early, continuous recording using either standart EEG or aEEG
- Ultra sonographic scan: easy and early but non specific
as early as possible
Short term prognosis. Therapeutic management: HYPOTHERMIA?
- MRI: standard sequences + Diffusion +/- DTI + MRSpectroscopy:
between day 3 and day 8 +/- day 10-15
Long term outcome.

7. Amplitude EEG features in HIE

8. HIE and MRI features
normal
- Basal ganglia and thalami
- Cortical enlighting
- Post limb of internal capsule
- White matter
Rutherforf et al., Lancet 2010

9. Potential pathways for HIE-induced injury
Perlman J M Pediatrics 2006;117:S28-S33

10. HIE and energy failures
• First energy failure during HIE
• Rapid recovery
• Secondary energy failure after
6-12h post HIE
• Mitochondrial insult
• Cell death and apoptosis

11. Brain metabolism is normal following
resuscitation but deteriorates later
31P MRS in asphyxiated infant
born at 37 weeks gestation
Azzopardi et al. Pediatr Res 1989;25:445-451)

12. Hypothermia: concept
• To induce a stable central temperature around 33.5°C +/- 0.5°C
• Before 6 hours of life
• In the most stable manner
• For a 72h duration
• Progressive and cautious rewarming 0.2°C / h

13. Hypothermia:
A post-conditioning concept
Post-Cond
Dirnagl et al., 2009

14. Hypothermia: cellular effects
Reduces cerebral metabolism, prevents edema
Decreases energy utilization
Reduces/suppresses cytotoxic amino acid accumulation
(glutamate) and nitric oxide
Inhibits platelet-activating factor, inflammatory cascade
Attenuates secondary neuronal damage and cell death
Reduces extent of brain damage
Prevention of blood brain barrier dysruption

15. Experimental evidence supporting
therapeutic hypothermia
Hypothermia applied after HIE:
Reduces elevation of dopamine, free fatty acid and glutamate
Stroke 1989 ;20:904-10.
Preserves cerebral energy metabolism
Pediatr Res 1995 ;37:667-670; Pediatr Res 1997 ;41:803-808
Reduces the delayed increase in extracellular glutamate
Neuroreport 1997 ;8:3359-62
Reduces the secondary rise in cortical impedance (cytotoxic oedema)
Pediatrics 1998 ;102:1098-1106
Inhibits apoptotic cell death
Neuropathol Appl Neurobiol 1997 ;23:16-25

16. Hypothermia
Head cooling
or
total body cooling

17. Hypothermie: monitoring is crucial
Brain regional temperatures
in pigglet Temperature stability according to
devices
Seizures during
rewarming
Thoresen et al., 2008

18. Acidosis
Hypothermia in human: Who? •pH≤7
•Base deficit ≥16 mmol/l
•Lactate ≥11 mmol/l
•Perinatal event leading to HIE or
•GA ≥ 36 wg et BW ≥ 1800 g
Apgar score ≤5 à M5
•Postnatal age < 6 hours
or
No spontaneous breathing
at M10
Biological and/or clinical markers for HIE at birth? or
Rescucitation at birth
YES
Clinical signs of HIE (Sarnat)
Clinical signs of neurological disorder linked to HIE?
YES
If possible, abnormalities:
• EEG
• aEEG (staging)
Therapeutic hypothermia

19. Hypothermia and biological markers
Heart rate: 14 bpm/min
PaCO2: 2 mmHg
pH: 0,12 unité
Leak of NaCl, KCl and Mg2+
blood viscosity
Platelets
Insulin resistance
WBC
Pharmacokinetics of morphine and anti-epileptic drugs

20. Beneficial effect of hypothermie
according to HIE severity
NNT 6-8
Tagin et al., Cochrane 2012

21. Beneficial effect of hypothermie
according to cooling technique
Tagin et al., Cochrane 2012

22. Normal outcome following
hypothermia for HIE
Tagin et al., Cochrane 2012

23. Impact of hypothermia on MRI findings
Therapeutic hypothermia makes
Therapeutic hypothermia reduces basal
ganglia and WM lesions… MRI abormalities more specific to
poor outcome
… but has no effect on cortical damage
Rutherford et al., 2009

24. Mid- long-term outcomes:
neurocognitive/behavior scales
12-30 months: Bayley
(Eicher & al., 2004; Jacobs & al., 2011; Shankaran & al., 2005)
6-7 years: WPPSI-III / WISC-IV / NEPSY / M-ABC
(Marlow & al., 2005; Shankaran & al., 2012)
9-10 years: WISC-III / M-ABC / CBCL
(de Veries & Jongmans, 2010)

25. Chilhood outcomes after hypothermia
for HIE
Objective
Long term evaluation (6-7 y) of infants having experienced
hypothermia for HIE
Methods and patients
208 infants with HIE 2-3 at birth
93 controls (6 y 8 m) vs 97 hypothermia( 6 y 7 m)
18 lost (15% of surviving)
Motor : GMFCS / Intellect : WPPSI-III & WISC-IV / Attention, FE, Visuo-
spatial : NEPSY / Emotional & Social : Child Health Questionnaire
Shankaran et al., NEJM 2012

26. Chilhood outcomes after
hypothermia for HIE
Results
Hypothermia ( n = 97)
27 deaths (28 %)
5 lost (5 %) death lost CP
12/69 CP (17 %) blindness deafness
1/67 blindness (1 %)
3/63 deafness (5%) 50
Controls (n = 93) 40
41 deaths (44 %) (%)
30
13 lost (14 %) 20
15/52 CP (29 %) 10
2/50 blindness (4 %) 0
1/50 deafness (2%) Hypothermia Controls
Shankaran et al., NEJM 2012

27. Chilhood outcomes after
hypothermia for HIE
Results
Hypothermia
19/70 IQ < 70 (27 %)
2/48 dysexecutive functions (< 70) (4 %)
2/53 visuo-spatial impairment (< 70) (4 %)
Controls
17/52 IQ < 70 (33 %)
4/32 dysexecutive functions (< 70) (13 %)
1/36 visuo-spatial impairment (< 70) (3 %)
Shankaran et al., NEJM 2012

28. Chilhood outcomes after
hypothermia for HIE
Interpretation
No significant difference:
CP
IQ at 6-7 y
Emotional skills
15% lost of follow up
Behavior and school performances?
Appropriate scales?

29. Hypothermia + neuroprotective agents
Robertson et al., 2012

30. Promising candidate molecules to be
associated with hypothermia
From Robertson et al., 2012

31. Hypothermia and melatonine
Anti-oxidant, anti-excitotoxic Melatonin in neonatal rat models of
and anti-inflammatory agent HIE
High inocuity Reduced lesion score
(p<0,05)
Reduced ROS accumulation
(p<0,05)
Better behavioral scores
(p<0,05)
Fulia F et al, J Pineal Res 2001; 31(4):343-9
Signorini C et al, J Pineal Res 2009; 46(2):148-54
Carloni S et al, J Pineal Res 2008; 44(2):157-64
Gitto E et al, J Pineal Res 2009; 46(2):128-39

32. Hypothermia and inhaled Xenon
Synergistic effect of hypothermia in pre-clinical model using hypothermia (32°C) and inhaled
Xenon (50%) (rats subjected to HIE) :
Hypothermia alone was associated with early and long-term behavior improvement
(p<0.001)
Xenon alone was associated with long-term behavior improvement (p<0.05)
Both hypothermia and Xenon were associated with better histological scores (p<0.05)
Hobbs C et al., Stroke 2008; 39:1307-
13

33. Deleterious co-factors to be avoided
Prevention of additional insult :
Pain
Subclinical seizures
Neurosensory dystimulation
Ionic disorders
Adequat use of oxygen
Rewarming
Developmental care

34. Conclusion
HIE trigger is poorly understood public health issue
More than 1M deaths and 2M infants with neurocognitive
impairments / year
Therapeutic hypothermia is feasible, safe in referral centers
and efficient at mid-term if initiated before 6h of life
… but impact in long-term outcomes?
Hot topics for neuroprotective strategies
… the future combination of hypothermia + other
pharmacological agent(s)