1. Dr Julia Uffindell Consultant Neonatologist

2. Cooling 'cure' averts infant brain damage Hi-tech 'ice pack' helps to protect newborns starved of oxygen through suffocation Cooling ‘cuts baby brain damage’ Moderate Hypothermia to Treat Perinatal Asphyxial Encephalopathy Volume 361(14):1349-1358. October 1, 2009

3.  Case Report – highlighting use of NPEU TOBY Register criteria and guidelines for Cooling  Discussion about rationale and evidence for Therapeutic Neonatal Hypothermia

4.  38+1 weeks gestation  Birth weight 4460g (99.6 th centile)  Born at a hospital with level 2 NNU  Mother: 22 years, white British, unemployed  Insulin dependent Diabetes Mellitus  Past obstetric history: Miscarriage at 11/40  Antenatal screening serology negative  Group B streptococcus on HVS this pregnancy (intrapartum antibiotics given)  Father 32 years, white British, unemployed  Parents not consanguineous

5.  Spontaneous vaginal delivery  Shoulder dystocia – 7 mins delay between delivery of head and body  Apgar score 0 at 1 minute  Resuscitation included inflation breaths, ventilation breaths, cardiac massage, intubation. HR > 100 at 7 mins  Apgar score 2 at 5minutes, 4 at 10 mins  Cord gas: pH 7.096, pO 2 1.52, pCO 2 10.74, BE -7.5

6.  Ventilated – relatively low pressures, soon stable in air  Blood cultures & started high dose broad spectrum antibiotics in view of history of GBS  Hypoglycaemia  Generalised tonic clonic seizures noted – requiring 2 X Phenobarbitone  Hypotension – requiring inotropes  Diagnosis: Presumed Hypoxic Ischaemic Encephalopathy – fulfilling criteria for Therapeutic Hypothermia

7. Criteria A Infants > 36 weeks admitted to NNU with at least one of the following: Apgar score of < 5 at 10 mins of age Continued need for resuscitation, including ET or mask ventilation at 10 mins of age Acidosis within 60 mins of birth (defined as any occurrence of umbilical cord, arterial or capillary pH <7.00) Base deficit > 16 in umbilical cord or any blood sample (arterial, venous or capillary) within 60 mins of birth

8. Criteria B If infant meets criteria A, assess for criteria B Seizures OR Moderate to severe encephalopathy, consisting of: Altered state of consciousness (reduced or absent response to stimulation) AND Abnormal tone (focal or general hypotonia or flaccid) AND Abnormal primitive reflexes (weak or absent suck or Moro).

9.  1 hour of age – Passive cooling commenced  Cooling centre contacted. NTS contacted  Changed from axillary to rectal temperature monitoring  2 hours of age – rectal temp 35.1  3 hours of age – rectal temp 36.3  3 hours 40 mins – Transport team commenced active cooling using cold water gloves  7 hours of age – target rectal temp of 33-34 0 C achieved  8 hours of age – arrived at Cooling Centre – active cooling using cooling mattress commenced

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12.  Ventilated on low pressures in air  No further seizures  Blood and CSF cultures negative  CFM trace on day 1– moderately abnormal - no seizure activity  CFM normalised on day 2  Cranial ultrasound scan on day 1 – cerebral oedema

13.  Day 2 - Hypotension resolved  Day 3 - Extubated – self ventilating in air  Cooling continued for 72 hours then slow rewarming (0.5 0 C per hour)  Day 4 – weak gag reflex present – started NG feeds  Day 5 – gag reflex improved – started breast feeds  Day 7 – full sucking feeds achieved - MRI scan normal  Day 8 – discharged home

14.  1 – 3 per 1000 live full term births  15-20% die in the postnatal period  25% of survivors - severe & permanent neuropsychological sequelae, including mental retardation, visual dysfunction, increased hyperactivity, cerebral palsy & epilepsy.  Outcomes are devastating & permanent - major burden for the patient, family & society.  Urgent need to identify & develop therapeutic strategies to reduce brain injury in newborns with H.I.E

15. Neuropathology of H.I.E. Hypoxia and/or ischaemia Inadequate glucose & oxygen supply Primary energy failure = Primary neuronal death Reperfusion - Cytotoxic mechanisms Further oxidative stress damage = Delayed neuronal death

16. Therapeutic Hypothermia 1hour 6 hours 5 days 11 Cytotoxic Mechanisms Hypothermia Delayed Neuronal Death Primary Death Hypoxia- Ischaemia Asphyxia

17.  Decreases metabolic need  Maintains ATP, inhibits secondary energy failure  Stops or reduces many damaging processes  Reduced inflammatory responses  Seizures during hypothermia may be less damaging than during normothermia

18.  Randomised to Intensive Care alone or Intensive care plus Total body cooling to 33-34 0 C for 72 hours then slow rewarming by 0.5 0 C per hour  Continuous rectal temperature monitoring  Primary outcome: Combined death & severe neurodevelopmental disability at 18 months  Secondary outcomes

19. TOBY Trial results OutcomeHypothermia (%) Normothermia (%)P value Primary outcome: Combined death & severe neurodisability 4553 (Note: predicted 70) 0.17 Secondary outcomes (significant) Survival without neurologic abnormality 44280.003 Cerebral palsy 28410.03 Improvements in other neurological outcomes in cooled group were not significant Adverse events were mostly minor and not associated with cooling

20.  TOBY trial: 131 scans from 325 infants available  MRI performed at 7-10 days  PPV = 84% non-cooled  PPV = 86% for cooled  MRI is valid as a predictor after hypothermia treatment  Basal ganglia–thalamus pattern +/- cortical injury  Abnormal signal intensity within posterior limb of internal capsule (PLIC) predicts abnormal motor outcome Sensitivity = 0.9 Specificity = 1.0 (Rutherford et al Pediatrics 1998)

21. MRI after H.I.E. de Vries L S, Jongmans M J Arch Dis Child Fetal Neonatal Ed 2010;95:F220-F224 Copyright © BMJ Publishing Group Ltd & Royal College of Paediatrics and Child Health. All rights reserved.