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Therapeutic hypothermia forneonatal hypoxic-ischemicencephalopathy           Olivier BAUD           Réanimation et Pédiatr...
HIE in the world          Major public health issue          23% of the total 4 M deaths in the world          20% of glob...
Etiologies of HIE    Maternal                            Fetal       Cardiac arrest                      Fetomaternal haem...
HIE severity and morbidity/mortality    Moderately severe                          Severe1-3 / 1000 livebirths            ...
Sarnat & Sarnat staging (1976)                        Stage 1               Stage 2                 Stage 3Consciousness  ...
Early evaluation of HIE•   Early and repeated clinical examination: Classification de Sarnat et Sarnat    staging+++•   Cl...
Amplitude EEG features in HIE
HIE and MRI features                                  normal- Basal ganglia and thalami- Cortical enlighting- Post limb of...
Potential pathways for HIE-induced injury                               Perlman J M Pediatrics 2006;117:S28-S33
HIE and energy failures                          • First energy failure during HIE                          • Rapid recove...
Brain metabolism is normal followingresuscitation but deteriorates later  31P MRS in asphyxiated infant  born at 37 weeks ...
Hypothermia: concept• To induce a stable central temperature around 33.5°C +/- 0.5°C• Before 6 hours of life• In the most ...
Hypothermia:A post-conditioning concept     Post-Cond                              Dirnagl et al., 2009
Hypothermia: cellular effects Reduces cerebral metabolism, prevents edema Decreases energy utilization Reduces/suppresses ...
Experimental evidence supportingtherapeutic hypothermia Hypothermia applied after HIE:    Reduces elevation of dopamine, f...
Hypothermia       Head cooling             or     total body cooling
Hypothermie: monitoring is crucialBrain regional temperaturesin pigglet                        Temperature stability accor...
AcidosisHypothermia in human: Who?                                    •pH≤7                                               ...
Hypothermia and biological markers Heart rate:      14 bpm/min PaCO2:      2 mmHg pH:      0,12 unité Leak of NaCl, KCl an...
Beneficial effect of hypothermie        according to HIE severity                                           NNT 6-8Tagin e...
Beneficial effect of hypothermie          according to cooling techniqueTagin et al., Cochrane 2012
Normal outcome following        hypothermia for HIETagin et al., Cochrane 2012
Impact of hypothermia on MRI findings                                         Therapeutic hypothermia makesTherapeutic hyp...
Mid- long-term outcomes:neurocognitive/behavior scales   12-30 months: Bayley     (Eicher & al., 2004; Jacobs & al., 2011;...
Chilhood outcomes after hypothermiafor HIEObjective  Long term evaluation (6-7 y) of infants having experienced  hypotherm...
Chilhood outcomes afterhypothermia for HIE Results    Hypothermia ( n = 97)         27 deaths (28 %)         5 lost (5 %) ...
Chilhood outcomes afterhypothermia for HIEResults  Hypothermia    19/70 IQ < 70 (27 %)    2/48 dysexecutive functions (< 7...
Chilhood outcomes afterhypothermia for HIE Interpretation   No significant difference:      CP      IQ at 6-7 y      Emoti...
Hypothermia + neuroprotective agents                              Robertson et al., 2012
Promising candidate molecules to beassociated with hypothermia                              From Robertson et al., 2012
Hypothermia and melatonine         Anti-oxidant, anti-excitotoxic              Melatonin in neonatal rat models of        ...
Hypothermia and inhaled Xenon Synergistic effect of hypothermia in pre-clinical model using hypothermia (32°C) and inhaled...
Deleterious co-factors to be avoidedPrevention of additional insult :   Pain   Subclinical seizures   Neurosensory dystimu...
Conclusion HIE trigger is poorly understood          public health issue More than 1M deaths and 2M infants with neurocogn...
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Therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy

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International conference «Actual approaches to the extremely preterm babies: International experience and Ukrainian realities» (Kyiv, Ukraine, March 5-6, 2013)

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Transcript of "Therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy"

  1. 1. Therapeutic hypothermia forneonatal hypoxic-ischemicencephalopathy Olivier BAUD Réanimation et Pédiatrie Néonatales INSERM U676 DHU PROTECT Hôpital Robert Debré, APHP International Neonatology Conference Kiev 6th March 2013
  2. 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 millionLawn JE et al, Lancet 2005
  3. 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. 4. HIE severity and morbidity/mortality Moderately severe Severe1-3 / 1000 livebirths 0.5-2 / 1000 livebirths Neonatal mortality: 50-75%Severe handicaps: 30-50% (epilepsy, Severe handicaps: 80%cognitive impairment, CP…) cccccMild handicaps: 10-20% Mild handicaps: 10-20%Normal outcome at 2y: 30-40% Normal outcome at 2y: 10%
  5. 5. Sarnat & Sarnat staging (1976) Stage 1 Stage 2 Stage 3Consciousness hyperalert Lethargic of obtunded Stupor or comaActivity Normal Decreased AbsentNeuromuscular control Muscle tone Normal Mild hypotonia Flaccid Posture Mild distal flexion Strong distal flexion Intermittent decerebration Strech reflexes Overactive Overactive Decreased or absentPrimitive reflexes Suck Weak Weak or absent Absent Moro Strong Weak, incomplete Absent Tonic neck Slight Strong AbsentAutonomic function Pupils Normal Miosis Mydriase or variable, unequal Heart rate Tachycardia Bradycardia VariableSeizures None Common UncommonStage 0 = Normal
  6. 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. 7. Amplitude EEG features in HIE
  8. 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. 9. Potential pathways for HIE-induced injury Perlman J M Pediatrics 2006;117:S28-S33
  10. 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. 11. Brain metabolism is normal followingresuscitation but deteriorates later 31P MRS in asphyxiated infant born at 37 weeks gestation Azzopardi et al. Pediatr Res 1989;25:445-451)
  12. 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. 13. Hypothermia:A post-conditioning concept Post-Cond Dirnagl et al., 2009
  14. 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. 15. Experimental evidence supportingtherapeutic 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. 16. Hypothermia Head cooling or total body cooling
  17. 17. Hypothermie: monitoring is crucialBrain regional temperaturesin pigglet Temperature stability according to devices Seizures during rewarming Thoresen et al., 2008
  18. 18. AcidosisHypothermia 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 M10Biological 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. 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. 20. Beneficial effect of hypothermie according to HIE severity NNT 6-8Tagin et al., Cochrane 2012
  21. 21. Beneficial effect of hypothermie according to cooling techniqueTagin et al., Cochrane 2012
  22. 22. Normal outcome following hypothermia for HIETagin et al., Cochrane 2012
  23. 23. Impact of hypothermia on MRI findings Therapeutic hypothermia makesTherapeutic hypothermia reduces basalganglia and WM lesions… MRI abormalities more specific to poor outcome… but has no effect on cortical damage Rutherford et al., 2009
  24. 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. 25. Chilhood outcomes after hypothermiafor HIEObjective Long term evaluation (6-7 y) of infants having experienced hypothermia for HIEMethods 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. 26. Chilhood outcomes afterhypothermia 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. 27. Chilhood outcomes afterhypothermia for HIEResults 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. 28. Chilhood outcomes afterhypothermia 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. 29. Hypothermia + neuroprotective agents Robertson et al., 2012
  30. 30. Promising candidate molecules to beassociated with hypothermia From Robertson et al., 2012
  31. 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):343-9Signorini C et al, J Pineal Res 2009; 46(2):148-54Carloni S et al, J Pineal Res 2008; 44(2):157-64Gitto E et al, J Pineal Res 2009; 46(2):128-39
  32. 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. 33. Deleterious co-factors to be avoidedPrevention of additional insult : Pain Subclinical seizures Neurosensory dystimulation Ionic disorders Adequat use of oxygen Rewarming Developmental care
  34. 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)
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