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Therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy
- 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)