Cooling Therapy in Neonatal Encephalopathy The unfinished Story - - PowerPoint PPT Presentation

Cooling Therapy in Neonatal Encephalopathy The unfinished Story

Sudhin Thayyil MD, FRCPCH, PhD

Head of Academic Neonatology Director, Centre for Perinatal Neuroscience Imperial College London, UK

2 Contents

• A. Recap of the cooling story so far
• B. Ongoing work

– Magnetic Resonance Biomarkers – Magnetic Resonance Biomarkers – Transcriptomic signatures – HELIX trial

3

4

Healthy Control HIE – Normothermic HIE – Cooled

5 Clinical trials

Cool cap Trial: Lancet 2005 (Auckland and Imperial College London)

NICHD (USA) Trial: NEJM 2005 TOBY Trial: NEJM 2009 (Imperial College London)

6 10 years…and still doesn’t work in all !!!

• 1. How can we speed up?

CONTENTS

• 2. Why doesn’t it work in all?

7 MR Imaging in neonatal encephalopathy

8 Proton MR spectroscopy

normal

Lac Naa

severe HI

Naa Lac Cho Lac Cr

9 Which MR Biomarker

Thayyil et al., Pediatrics 2010

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MARBLE (Magnetic Resonance Biomarkers in neonatal Encephalopathy) Can MR biomarkers accurately predict neurological outcome 2 years in a multicenter setting? – MR spectroscopy (metabolic injury) – Diffusion MRI (microstructural injury) – Diffusion MRI (microstructural injury) – ‘Conventional’ structural MRI

• 223 babies from 8 centres in the UK and USA over 3 years
• Bayley III at 2 years of age

Lally et al., BMJ Open 2016

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MARBLE (Magnetic Resonance Biomarkers in neonatal Encephalopathy)

12 Use in future clinical trials

NAA: Surrogate endpoint arm Neurodevelopment as endpoint r arm Power No per arm Power No per ar

(Mean difference 2.5 mmol/kg, SD 2.) (CER 50%, RRR 20%, alpha 0.05)

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Co-existent infection and FIRS Maternal illness Growth restriction

Clinical Heterogeneity

Encephalopathy Cerebral Palsy Hypoxia- Ischemia Acute versus Sub acute hypoxia

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Can transcriptomic signature aid in disease stratification at birth?

Number of gene copies (up and down) ‘signature’

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NE Babies Controls NE infants

Transcriptomic signature

Controls total 6305 genes adj pvalue<0.05

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Transcriptomic signature

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1 million deaths per year from neonatal encephalopathy

Why do a cooling trial in LMIC?

Lawn et al., Lancet 2005

18 Why do a cooling trial in LMIC?

• Clinical heterogeneity

– Population differences – Nature and origins of brain injury – Higher perinatal infection & other co-morbidities – Higher perinatal infection & other co-morbidities

• Sub optimal intensive care

– Public sector versus Private sector issues – Lack of effective transport system

19 Why do a cooling trial in LMIC?

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21 Phase Change Material for Cooling

54 babies with mild, moderate or severe encephalopathy born at Calicut Medical College, Kerala Thayyil et al., Arch Dis Childhood 2007

22 HELIX feasibility study

• 1. Connect Tecotherm Helix to the

electric supply via the power unit

• 2. Connect T

ecotherm Helix to the mattress using the hose

I 2

T ecotherm-Helix Set up

• 3. Add pre-mixed

coolant till the fluid level is visible (first use only)

• 5. Add more pre-mixed coolant

holding the mattress vertical so that the air bubbles escape and mattress is fully filled with fluid

• 4. Switch on the machine

Keep baby on the mattress, Attach the rectal probe to tecotherm helix (red arrow) Insert the rectal probe (4 to 6 cm) (blue arrow) Wrap the mattress around the baby using a small tape (non-sticking) through the mattress eye hole (black arrow) (green arrow)

• 6. Keep a thin cloth over the mattress

3 5 7 6 4

Oliveira et al., BMJ Ped Open 2018

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• To examine the feasibility of whole body cooling using a servo

controlled cooling device (Tecotherm HELIX) and short term neonatal morbidity

• 82 babies with moderate or severe encephalopathy recruited from 4

HELIX feasibility study

• 82 babies with moderate or severe encephalopathy recruited from 4

centres in India

• 22% babies died

Oliveira et al., BMJ Ped Open 2018

24 HELIX feasibility study Survivors (n=67) Non-survivors (n=15) P-value Gestational age (weeks) 38.8 ± 1.3 38.0 ± 1.2 0.14 Age at start of cooling (hours) 3.6 ± 1.4 4.1 ± 1.4 0.22 Birth weight (g) 2912 ± 364 2855 ± 388 0.58 10 min Apgar 5.5 ± 0.8 5.0 ± 1.0 0.36 Severe encephalopathy 11/67 (16%) 10/15 (67%) <0.001 Seizures within 6 h of birth 55/64 (86%) 13/14 (93%) 0.68 Place of delivery Inborn 15/65 (23%) 4/13 (31%) Inborn 15/65 (23%) 4/13 (31%) Outborn – hospital 48/65 (74%) 9/13 (69%) 0.81 Outborn – home 2/65 (3%) 0/13 (0%) Neonatal complications Gastric bleeds 14/38 (37%) 11/11 (100%) <0.001 Pulmonary haemorrhage 1/38 (3%) 5/11 (45%) 0.001 PPHN 1/38 (3%) 6/11 (55%) <0.001 Thrombocytopenia 42/67 (63%) 10/15 (67%) 1.00 Metabolic acidosis 26/67 (39%) 9/15 (60%) 0.16 Treatment duration (days) Invasive ventilation 1.4 ± 1.8 3.3 ± 1.5 0.002 Sedation 0.9 ± 1.5 1.4 ± 1.8 0.40 Inotropic support 3.1 ± 1.3 3.9 ± 0.3 0.04 Anticonvulsive drugs 2.9 ± 1.7 3.9 ± 0.3 0.07

Oliveira et al., BMJ Ped Open 2018

25 HELIX feasibility - Heart rate and Mortality

Oliveira et al., BMJ Ped Open 2018

26 HELIX – Main Trial

Primary

• To examine whether whole body cooling to 33.5˚ C initiated within 6

hours of birth and continued for 72 hours reduces death or neurodisability at 18 to 22 months after neonatal encephalopathy in a ‘real life setting’ in low and middle-income countries. ‘real life setting’ in low and middle-income countries. Secondary

• Proton MR spectroscopy Thalamic N-acetyl aspartate level and white

matter fractional anisotropy at 1 week

• Host gene expression profile
• Perinatal infection

Thayyil et al., BMJ Open 2017

27 Study design and Centers

• 408 babies with moderate or severe encephalopathy

– Sion – Mumbai (J Mondkar) – IGH Bangalore (N Benkappa) – ICH, Madras Medical College (Mangalabharathi) – IOG, Madras Medical College (Aresar) – SAT, Trivandrum (Radhika) – MAMC, New Delhi (Ramji) – Kelaniya, Sri Lanka (Rodrigo) – BSMMU, Dhaka (Shahidullah)

• Babies randomized (web-based) to whole body cooling (Tecotherm)

for 3 days or usual care

• 3T MR imaging and spectroscopy within 2 weeks
• Detailed infection screening and transcriptomics
• Bayley III at 18 to 22 months

Thayyil et al., BMJ Open 2017

28 HELIX so far

• 288 babies recruited since Aug 2015 (12 to 15 babies per month)
• Expected to complete recruitment (120 more) by October 2018
• All recruited cases surviving till 2 weeks had MRI and MRS
• Follow up is challenging
• Follow up is challenging

– Frequent changes in mobile numbers – Migrant families and slum population – Despite this, all except one family in contact – Often the team visited homes, slums, had to fly to different states – Second (external team) for parents upset with recruiting centers

• Highly committed team and MAJOR team effort

29 Survey of Cooling in Indian Neonatal Units

Hospitals participated in the survey Public (n=25) Private (n=68) Total (n=93) Offers cooling as standard care 10 (21%) 37 (79%) 47 (51%) Offers cooling as standard care 10 (21%) 37 (79%) 47 (51%) Do not offer due to lack of cooling devices and trained staff 13 (52% 28 (41%) 41 (44%) Do not offer as strong evidence from clinical trials are lacking 2 (8%) 3 (4%) 5 (5%)

Chandrasekeran, Swamy et al., Indian Pediatrics 2018

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Hospitals offering therapeutic hypothermia Public (n=10) Private (n=37) Total (n=47)

Cooling devices Approved cooling devices* 9 (90%) 13 (35%) 22 (47%) Indigenous cooling solutions** 1 (10%) 24 (65%) 25 (53%) Initiation of cooling

Survey of Cooling in Indian Neonatal Units

Initiation of cooling Within 6 hours after birth 10 (100%) 28 (76%) 38 (81%) Upto 12 hours after birth 0 (0%) 7 (19%) 7 (15%) Upto 24 hours after birth 0 (0%) 2 (5%) 2 (4%) Sedation during cooling Intravenous sedation 6 (60%) 20 (54%) 26 (55%) Oral sedation only 2 (20%) 2 (5%) 4 (9%) None 2 (20%) 15 (41%) 17 (36%)

Chandrasekeran, Swamy et al., Indian Pediatrics 2018

31 Take home messages

• Cooling (33 to 34 C) within 6 h of age for 72 h improves survival

without disability after moderate or severe encephalopathy in high income countries

• Safety and efficacy of cooling in LMIC is not known, and hence this
• Safety and efficacy of cooling in LMIC is not known, and hence this

therapy should be considered experiential, until the HELIX trial data is available.

• MR spectroscopy biomarkers and transcriptomic profile will help speed

up the clinical translation of novel therapies and personalized neuroprotection

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Thankyou