Predicting Outcomes in HIE. Naaz Merchant Consultant Neonatologist Beds & Herts Meeting 17/03/2016

Transcription

1 Predicting Outcomes in HIE Naaz Merchant Consultant Neonatologist Beds & Herts Meeting 17/03/2016

2 Interactive please!

3 Case 1 Term, 3.5 kg Antenatal: Breech Labour/Delivery: Em CS failure to progress, mec Resus: First gasp at 10 min, HR>100 at 6 min Apgars: 1, 1, 5 Cord gas ph 6.9 BE -15 (a & v) Cooled 72 hrs, seizures till D2 CFM background abnormal on D4 MRI basal ganglia high signal, abn myelin in PLIC

4 Case 1

5 Prognostic assessment Counselling parents Considering redirecting care Early intervention Community referral Follow up (2/6 year outcomes) Neuroprotective intervention research Influence of cooling??

6 Prognostic indicators Condition at birth Assessment of encephalopathy aeeg Neuroimaging Neurophysiological tests Biomarkers

7 Assessing Prognostic Indicators Test Outcome Positive Test Outcome Negative Condition Positive True Positive (TP) False Negative (FN) Sensitivity TP / (TP + FN) Condition Negative False Positive (FP) True Negative (TN) Specificity TN / (FP+TN) PPV TP / (TP + FP) NPV TN / (FN + TN)

8 Apgar score I. Clinical assessment at birth At 5 or 10 minutes Blood gas analysis ph, base deficit or serum bicarbonate Need and duration for resuscitation Delayed onset of respiration

9 Clinical Prognostication Individually they have poor predictive accuracy Low sensitivity and PPV but high specificity and NPV when assessed very soon after birth Combination of clinical variables is more predictive of subsequent outcome

10 Prognostic measures in 1 st week Sensitivity Specificity OR (95%CI) PPV NPV HR 5min < ( ) SatO2 5 min < ( ) Apgar 5min < ( ) HIE ( ) Umbilical a ph 8 96 Lactate 5 96 Saugstad OD Acta Pediatr 2005 Moster D J.Pediatr 2001 Ruth VJ BMJ 1988

11 Stepwise Prediction Rule- Combination Chest compressions >1 minute; onset of breathing >30 minutes; base deficit value >16 Absence of all 3 variables reduced the probability of severe adverse outcome by 20% Shah et al. Arch Pediatr Adolesc Med. 2006

12 Cooling- NIHCD min was 0-3: rates of death/disability at 6-7 years was 75% 10 min >3: rate of death/disability 45% The test of interaction between cooling & Apgars was not statistically significant, suggesting that the therapeutic effect of cooling is not dependent on the Apgar score in the first few minutes after birth

13 Sarnat score Modified scores Issues II. Clinical assessment Difficulty measuring some components reliably soon after birth (eg primitive reflexes, breathing and seizures in sedated or paralysed ventilated infants) Occurrence of intermediate signs Variable state of encephalopathy in first 72 hours

14 Cooling & Clinical HIE improved steadily over the first 4 days in the cooled group whilst improvement occurred later in the noncooled (NIHCD/TOBY) NIHCD study: predicting death or disability was the grade of encephalopathy at 72 hours and at discharge Severe encephalopathy >72 hours associated with death/severe disability: 89% in the cooled & 100% in the non-cooled Moderate encephalopathy >72 hours had improved outcomes compared with non-cooled infants:69% vs 36%

15 Thompson score by survival n=546 (UK TOBY Register)

16 III. aeeg and HIE (Pre-cooling) aeeg is an excellent early predictor of neurological outcome aeeg in the first 24 hours: sensitivity of 93% (95% CI 85-97) and specificity of 91% (95% CI 67-98%) van Laerhoven 2013 Individual studies report a PPV >80% for death/disability Combining the grade of encephalopathy with aeeg further improves predictive accuracy Shalak 2003

17 aeeg and HIE -Predictor of Outcome aeeg changes depends on the duration and severity of the insult Recovery time is important as severity of abnormal aeeg correlates with neurological outcome Milder cases- rapid recovery of aeeg within 6-12 hrs and prognosis is excellent Prolonged intermediate abnormalities (moderately abnormal voltage or burst suppression pattern) have a more variable outcome A severely abnormal trace (flat trace or chronic low voltage pattern) > hours is associated with death or severe neurodevelopmental abnormalities

18 aeeg and HIE Predictor of Outcome van Laerhoven, H., et al., Pediatrics, (1): p

19 aeeg and HIE Predictor of Outcome Positive Predictive Value (%) Negative Predictive Value (%) Likelihood ratio Abnormal examination Abnormal aeeg Combination of abnormalities Shalak, L.F et al. Pediatrics, (2): p

20 aeeg and Cooling Not all the studies of hypothermia used aeeg as enrolment criteria aeeg is not an essential criteria for indication of hypothermia BUT: Useful for prognosis Identification of seizures (only 20% identified clinically, 40-45% with aeeg) Does cooling have an effect on aeeg recovery? Initial idea: Cooling is neuroprotective Should this result earlier recovery?

21 Predictive value of aeeg following hypothermia The predictive value of an early abnormal aeeg background is reduced with hypothermia which is consistent with the neuroprotective effect of hypothermia The recovery time to normal brain activity (±SWC) are useful prognostic indicators but longer in hypothermia

22 Predictive value of aeeg following hypothermia Infants who never regained a normal trace or SWC within the recording period are plotted inside the shaded bars All NT infants with good outcomes showed recovery by 24 hours All HT infants with good outcomes showed recovery by 48 hours No infant with good outcome had persistent abnormal brain activity beyond 48 hours Age when normal trace achieved plotted against age of onset of SWC Thoresen M, et al. Pediatrics Jul;126:e131-9.

23 Predictive value of aeeg following hypothermia PPV of an abnormal aeeg (BS, LV, or FT) to predict poor outcome (death/disability) is different in hypothermiatreated or normothermiatreated infants A severely abnormal trace (flat trace or chronic low voltage pattern) persisting more than hours is associated with a poor outcome Cseko, A.J., et al. Acta Paediatr, (7): p Thoresen, M., et al. Pediatrics, (1): p. e131-9.

24 aeeg Recovery in HIE + Cooling Cooling alters the prognostic value of the aeeg Recovery is slower with hypothermia treatment Cooled infants with good outcomes showed recovery by 48 hours A severely abnormal trace (flat trace or chronic low voltage pattern) at 48 hours is associated with death or severe neurodevelopmental abnormalities despite of hypothermia

25 Predictive ability of major MRI abnormalities for death or severe disability at 18 months Cooled Non-cooled Sensitivity 0 88 ( ) 0 94 ( ) Specificity 0 82 ( ) 0 68 ( ) Positive predictive value 0 76 ( ) 0 74 ( ) Negative predictive value 0 91 ( ) 0 92 ( ) Lancet Neurol Jan;9(1):39-45

26 Reduction in cerebral lesions on MRI Lesion Site (TOBY) Odds Ratio (95% CI) Basal ganglia and thalami 0.36 ( ) p=0.02 PLIC 0.38 ( ) p=0.02 White matter 0.30 ( ) p=0.01 Cortex 0.62 ( ) p=0.25

27 Acute hypoxic-ischaemic insult: basal ganglia and thalamic (BGT) lesions mild moderate severe BGT lesions give rise to cerebral palsy Severity of neonatal BGT lesion dictates severity of impairment* Martinez Biarge et al 2010

28 Posterior limb of the internal capsule (PLIC) in hypoxic ischaemic encephalopathy Loss of signal intensity Abnormal PLIC powerful predictor of motor outcome and later ability to walk ( PPV 0.88 NPV 1.0 ) sensitivity 1.0 specificity 0.7 Rutherford et al 1998 Martinez Biarge et al 2010

29 PLIC and ability to walk at age 2 years All children with normal signal intensity in the posterior limb of the internal capsule (PLIC) were walking independently by 2 years PLIC Not walking Walking Abnormal PPV = 0.88 Normal 0 23 NPV = 1.0 Sensitivity = 1.0 Specificity = 0.70 Martinez Biarge Neurology 2011

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33 Brainstem lesions and outcome (n=175) Martinez Biarge J paediatr 2012 T1 T1 T1 No brainstem injury (32%) Moderate brainstem injury (23%) Severe brainstem injury (45%) No deaths 25% died 49% died

34 Isolated WM injury at term Rare in HIE if a sentinel event i.e. not typical of an acute injury 1/48 (Okereafor) TOBY trial 0/40 severe WM and normal BGT. Exclude infection; viral, bacterial

35 Scoring system for white matter injury T2 T2 T2 T2 Normal WM Martinez Biarge et al EJPN 2012 Mild WM Exaggerated long T1/T2 in the PV WM only Moderate WM Long T1/T2 extending to the subcortical WM, or focal punctate lesions or focal area of infarction Severe WM Widespread abnormalities including overt infarction, haemorrhage and loss of grey matter/wm differentiation

36 Outcomes in isolated WM injury in HIE 67 children were evaluated with Griffiths at a median age of 29 months (range 12-56) Normal and mild WM n = 22 Moderate WM n = 28 Severe WM n =18 P Total DQ <0.001 Motor Social Language <0.001 Eye and Hand Coordination <0.001 Performance <0.001 * Martinez Biarge EJPN 2012

37 Hypothermia Does hypothermia alter pattern of lesions? Does it delay the onset or evolution of lesions? Does it decrease the number of lesions? Does it impair the ability of MR to predict outcome?

38 Hypothermia reduces tissue injury * Therapeutic hypothermia was associated with a reduction in: Basal ganglia or thalamus lesions (P=0.02) White matter lesions (P=0.01) Abnormal posterior limb of the internal capsule (P=0.02). Cooled infants: had fewer scans predictive of later neuromotor abnormalities (P=0.03) were more likely to have normal scans ( P=0.03). * Rutherford et al Lancet Neurol 2009

39 Prediction of outcome MRI performed at median of 8 days in both cooled and non cooled infants The accuracy of prediction by MRI of death or disability to 18 months of age was 0.84, 95% CI, in the cooled and 0.81, 95% CI, in the non cooled groups. * Rutherford et al Lancet Neurol 2009

40 Hypothermia Does hypothermia alter pattern of lesions? No Does it delay the onset or evolution of lesions? No Does it decrease the number of lesions? Yes Does it impair the ability of MR to predict outcome? No Same questions need to be asked for each new intervention e.g. TOBY/Xenon trial

41 Thank You Hope you enjoyed!