Queen Charlotte Hospital

Queen Charlotte Hospital

Neuroprotection for neonatal encephalopathy Neonatal encephalopathy accounts for 1 million deaths worldwide and even greater numbers of disabled survivors In countries with excellent maternity services NE occurs in 2-3/1000 births with 1-2/1000 developing moderate/severe NE Mortality is about 30% and disabilities occur in about 50% of survivors following moderate/severe NE Cognitive function may be impaired even in mild/moderate cases

Development of therapeutic hypothermia for perinatal asphyxial encephalopathy Academic research. Cooksey: A Review of UK Health Funding. 2006 Chart 7.1 Implementation Surveillance Audit

Study Cooled : Controls Gluckman (CoolCap trial) (2005) Shankaran, (NICHD trial) (2005) Azzopardi (TOBY trial)(2009) Cooling method Temp o C (core) Duration Cooling (hours) Primary outcome 116:118 Selective 34-35 72 Rate of death + severe disabilities 102:106 Systemic 33.5 72 Rate of death + moderate + severe disabilities 163:162 Systemic 33-34 72 Rate of death + severe disabilities Li (2010) 38:44 Systemic 33-34 72 Rate of death + severe disabilities Simbruner (neo.nneuro.netwo rk trial) (2010) 64:65 Systemic 33-34 72 Rate of death + severe disabilities Zhou 2010 119:116 Selective 34-35 72 Rate of death + severe disabilities Jacobs (ICE trial) (2011) 110:111 Systemic 33-34 72 Rate of death + severe disabilities Followup period 18 months 18 months 18 months 18 months 18 months 18 months 24 months

Does it work: death or severe disability to 18 months of age

Effect of therapeutic hypothermia on rate of intact survival at 18 months

Key neurological outcomes at 18-24 months following therapeutic hypothermia Death or disability Bayley MDI <70 Cerebral palsy Intact survival All P <0.01 Controls Cooled Risk ratio (95% CI) 405/675 298/671 0.74 (0.66-0.84) 110/324 89/370 0.71 (0.56-0.90) 150/437 108/497 0.64 (0.50-0.82) 109/483 174/487 1.58 (1.29-1.93) Number needed to treat (95% CI) 6 (4-9) 10 (6-25) 8 (6-14) 7 (6-14)

Outcome at 6-7 years (NICHD study) Primary Outcome: Hypothermia Control N=97 N=93 Death or IQ< 70 46/97 (47%) 58/93 (62%) Secondary Outcomes: Death 27/97 (28%) 41/93 (44%) Death or CP (moderate/severe) 38/92 (41%) 55/91 (60%) Adjusted RR (95% CI) 0.78 (0.61-1.01) 0.66 (0.45-0.97) 0.73 (0.55-0.98)

Cooling is now standard of care in UK infants with hypoxic ischaemic encephalopathy NICE guidance on cooling treatment for neonatal encephalopathy BAPM statement

The size of the problem in the UK Neonatal encephalopathy in a UK population (South London) 57159 women enrolled 150 cases with NE (92 with fits) 143 cases HI No seizures N=56 Seizures N=87 Annual births in UK: 750000 Expected No with HIE: 1875 Expected No with seizures: 1143 Incidence of HIE 2.5/1000 births 61% with seizures

UK TOBY Cooling Register WWW.NPEU.OX.AC.UK/TOBYREGISTER Protocol / Guidance / data forms

TOBY Register Cooling centres

Unanswered questions about cooling therapy Unlike pharma studies, dose, duration of treatment and indications not fully worked out in preliminary studies

Unanswered questions about cooling therapy Which infants should be cooled? Gestation range? Other asphyxial conditions? Metabolic disorders? What depth/duration of cooling? Is it safe to cool below 33C? Should cooling be extended beyond 72 hours When is treatment futile? Does cooling affect prognostic assessment?

Criteria for offering cooling A. Infants 36 completed weeks gestation admitted to the neonatal unit with at least one of the following: Apgar score of 5 at 10 minutes after birth Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth Acidosis within 60 minutes of birth (defined as any occurrence of umbilical cord, arterial or capillary ph <7.00) Base Deficit 16 mmol/l in umbilical cord or any blood sample (arterial, venous or capillary) within 60 minutes of birth B. Seizures or moderate to severe encephalopathy, consisting of: Altered state of consciousness (reduced response to stimulation or absent response to stimulation) and Abnormal tone (focal or general hypotonia, or flaccid) and Abnormal primitive reflexes (weak or absent suck or Moro response) Infants who meet criteria A and B may be considered for treatment with cooling.

Additional criteria

Recovery No encephalopathy Continue normothermia Resuscitation Follow standard NLS procedures Encephalopathy Start passive cooling and continuous temperature monitoring Step 1 Birth to 1 hour of age Passive cooling with continuous rectal or axillary temperature monitoring. Record temperature every 15 minutes. Start CFM monitoring. Step 2 1 to 6 hours of age Assess baby for treatment criteria A and B Criteria not met: Cooling not appropriate Start slow rewarming Criteria met: Inform parents Start active cooling

Key clinical characteristics of infants notified to the UK TOBY Cooling Register from December 2006 to July 2011 Characteristic n=1384 Gestational age at birth, weeks (n=1350) Median {IQR} [Range] Birth weight, grams (n=1379) Median {IQR} [Range] Age when cooling commenced, hours (n=1331) Median {IQR} [Range] 40 {38.4 to 41.1} [34.0 to 44.4] 3340 {2900 to 3800} [1530 to 5830] 3.3 {1.5 to 5.5} [0 to 35.3] Cooled before gestational age of 36 weeks, n (%) (n=1348) 38 (2.8) Outcome at discharge, n (%) (n=1362) Discharged home Transferred to a different hospital Died before discharge Outcome at 2 yrs, n (%) (n=226) Died after discharge and before 2 years Cerebral Palsy (n=206) 912 (67) 172 (13) 278 (20) 6 (3) 51 (25)

Percentage (95% CI) with clinical seizures 0 10 20 30 40 50 60 70 80 90 100 68.9 Clinial seizures by year of registration (n=1255) 60.6 65.7 2007 2008 2009 2010 2011 2012 Year of registration Chi-square test for trend (1 df) = 13.0, p<0.001 55.6 46.3 Percentage (95% CI) with severely abnormal aeeg 0 10 20 30 40 50 60 70 80 90 100 Severely abnormal aeeg by year of registration (n=1121) 53.8 43.1 39.6 2007 2008 2009 2010 2011 2012 Year of registration Chi-square test for trend (1 df) = 12.3, p<0.001 35.4 31.3 Apgar score at 10 minutes by year of registration (n=1113) 0 Base excess by year of registration (n=1167) Median (IQR) Apgar score at 10 minutes 0 1 2 3 4 5 6 7 8 9 10 4 4 5 5 5 2007 2008 2009 2010 2011 2012 Year of registration Non-parametric test for trend = 3.1, p=0.002 Median (IQR) base excess -30-25 -20-15 -10-5 -19.6-20 -17.9-17.3-16.8 2007 2008 2009 2010 2011 2012 Year of registration Non-parametric test for trend = 5.1, p<0.001 Change in clinical condition of infants reported to Register from 2007-2011

Clinical characteristics of infants notified to the UK TOBY Cooling Register and survival at discharge Characteristic Seizures before cooling commenced, n (%) (n=1263) Severely abnormal aeeg, n (%) (n=1129) Apgar score at 10 minutes, (n=1127) Median {IQR} Cord gas ph, (n=1298) Median {IQR} Base excess, (n=1175) Median {IQR} Thompson encephalopathy score, (n=551) Median {IQR} Alive at discharge (n=1084) Died before discharge (n=278) p value 585 (58%) 163 (64%) 0.09 251 (28%) 188 (81%) <0.001 5 {4 to 7} 3 {0 to 5} <0.001 6.9 {6.8 to 7.0} 6.8 {6.7 to 6.9} <0.001-17.2 {-21.0 to -13.6} -21.5 {-25.0 to -17.2} <0.001 8 {4 to 12} 15 {12 to 16} <0.001

Does cooling affect prognostic assessment? Cooling may alter prognostic value of clinical examination (Pediatr. 2008 Jan;152(1):55-8) Predictive value of aeeg altered by cooling (Pediatrics. 2010 Jul;126(1):e131-9) MRI is a good predictor of outcome (Lancet Neurol. 2010 Jan;9(1):39-45).

Effect of hypothermia by severity of encephalopathy

Therapeutic Hypothermia Changes the Prognostic Value of Clinical Evaluation of Neonatal Encephalopathy Moderate encephalopathy on day 4 after birth Favourable outcome Cooled group 31 14 Unfavourable outcome Non cooled group 12 21 Pediatr. 2008 Jan;152(1):55-8

Outcome following hypothermia by persisting encephalopathy Cooled infants Encephalopathy grade at day 4 Moderate encephalopathy Severe encephalopathy Good outcome 31/45 (69%) 3/28 (11%) Pediatr. 2008 Jan;152(1):55-8

Predictive value of clinical examination Clinical assessment of encephalopathy strongly associated with outcome A persistent (3-4 days) moderate encephalopathy does not exclude recovery following cooling A persistent (3-4 days) severe encephalopathy indicates a poor outcome despite cooling

PPV of an abnormal aeeg (BS, LV, or FT) to predict poor outcome (death/disability) in hypothermia-treated or normothermia-treated infants Thoresen M et al. Pediatrics 2010;126:e131-e139

Predictive value of aeeg within 6 hours of birth (TOBY trial data) PPV 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Cooled Not cooled Number 60 50 40 30 20 10 0 DDIS Not DDIS DDIS Not DDIS Cooled Not Cooled 0 Moderate Severe Norm/Mod Severe/ContSeiz DDIS= death or disability

Predictive value of aeeg within 6 hours of birth (TOBY trial data) 0,8 0,8 0,7 0,7 0,6 0,6 0,5 0,5 PPV 0,4 Cooled PPV 0,4 Cooled 0,3 Not Cooled 0,3 Not Cooled 0,2 0,2 0,1 0,1 0 Discont BS CLV FT 0 Disc/BS BS/CLV/FT CLV/FT

Predictive value of aeeg during 72 hours of cooling (unpublished data) PPV of aeeg PPV 1 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 6 12 18 24 36 48 60 72 CNV DNV BS CLV FT CLV+FT Hours after birth

Predictive value of aeeg following hypothermia A poor outcome following cooling occurs in about 33% of infants with a moderately abnormal trace (discontinuous/burst suppression pattern) and in about 60% of infants with a severely abnormal trace (flat trace or chronic low voltage pattern) within six hours after birth

Predictive value of aeeg following hypothermia A severely abnormal trace (flat trace or chronic low voltage pattern) persisting more than 24-36 hours is associated with a poor outcome in >90% of infants

Predictive ability of major MRI abnormalities during first 4 weeks after birth for death or severe disability at 18 months Cooled Non-cooled Sensitivity Specificity Positive predictive value Negative predictive value 0 88 (0 79 0 97) 0 82 (0 72 0 92) 0 76 (0 65 0 87) 0 91 (0 83 0 99) 0 94 (0 88 1 0) 0 68 (0 56 0 80) 0 74 (0 63 0 85) 0 92 (0 85 0 99) Data are proportions (95% CI). Major MRI abnormalities were defined as moderate or severe basal ganglia or thalamic lesions, severe white matter lesions, or an abnormal posterior limb of the internal capsule. Lancet Neurol. 2010 Jan;9(1):39-45

When is treatment futile? Combination of flat/low voltage EEG with stage 3 encephalopathy beyond 36-48 hours is ominous It may reasonable to redirect care before 72 hours of cooling therapy MRI could support clinical assessment

Summary Hypothermia is neuroprotective in neonatal asphyxial encephalopathy Effect is modest but very important clinically Organisation of local services and use of local protocols are necessary as cases occur unexpectedly and relatively infrequently Prospective surveillance of treatment with cooling may help refine treatment protocols