Dr Kumar Ankur Senior Consultant Neonatologist

BLK Superspeciality Hospital, DelhiNational Nursing Quiz Coordinator

HIE- Prevention & Newer Neuroprotection

Burden of Asphyxia- Long term

• Global Burden: 1-3/1000 live birth

• LMIC: 15 to 20 times high

LONG TERM OUTCOMES:

• High Rtae of CP- 28-82%

• Moderate & Severe NE survivors

–decreased IQ at 2-6 years

–School performance problems

–Autism spectrum disorders

–Schizophrenia

NNPD Database: 14/1000

3,65,000/year HIE

30% Neonatal Death

MILD HIE

25%

Development delay

Early Human Development 120 (2018) 80–87

Cerebral Injury Evolves over Hours to Days

Hypoxia-

ischemiaPrimary Cell-

Death Cytotoxic-

MechanismDelayed -

Neuronal deathSome neurons recover

partially

Apoptosis

Excitotoxic Injury

Inflammation

Oxidative stress

Mitochondrial failure

1

hour

6

hourDays

Timing

≈6 hours

Degree

3°C to 4°CDuration

≈72 hours

Cooling Trials

11 trials, 1500 + infants

Mortality + Major NDI @18 month

• RR 0.75 (95% CI 0.68 to 0.83)

• NNT: 7 (5,10)

Only Mortality

• RR 0.75 (95% CI 0.64 to 0.88)

• NNT: 11 (8,25)

Susan Jacob, Cochrane Database Syst Rev. 2013 Jan 31;(1):CD003311.

Neurocognitive outcome after TH

• TOBY trial follow up at 6-7 years

–Survival with IQ > 85 (RR-1.31 (1.01-1.71)

–Death- 29 % vs 30%

–IQ > 85 among survivors-77% vs. 63% (RR 1.22 (1.00-1.44)

• NICHD Study (Seetha Shankaran et al 2012)outcome at 6-7 years

–15 % less Death or mod /severe disability (RR 1.22 (1.00-1.44)

–34 % less death

Azzopardi et al. NEJM 2014; 371;2:140-149

NEJM 366;22 nejm.org may 31, 2012

Indian Data• Low cost alternative

• First RCT in India- JIPMER( 65 babies/6 month

development then CMC

• Multicentric study (safe , feasible)

HELIX trial (Hypothermia for encephalopathy in middle

& low income countries)

– 408 babies (India/Bangladesh/Srilanka)

– Primary outcome: Death or mod to severe disability

at 18 months

(Shruti K Bhardwaj & Visnu BHatt, Journal of Tropical Pediatrics Vol-58, 2012)

(Neonatology, Niranjan Thomas) /Indian Pediatr 2018;55: 201-205/

2007- 2015

Cool Gel to PCM

Safety

Indian Data• Low cost alternative

• First RCT in India- JIPMER( 65 babies/6 month

development then CMC

• Multicentric study (safe , feasible)

HELIX trial (Hypothermia for encephalopathy in middle

& low income countries)

– 408 babies (India/Bangladesh/Srilanka)

– Primary outcome: Death or mod to severe disability

at 18 months

(Shruti K Bhardwaj & Visnu BHatt, Journal of Tropical Pediatrics Vol-58, 2012)

(Neonatology, Niranjan Thomas) /Indian Pediatr 2018;55: 201-205/

2007- 2015

Cool Gel to PCM

Meta analysis - Low tech methods

• 3 trials involving 467 infanst

• Death before discharge - RR- 0.60 (0.39-0.92)

• Reduction in neurological morbidity- RR 0.46 (0.33-0.63)

• Decrease in mortality or severe morbidity at 24 months

– RR 0.77(0.62-0.98)

Rossouw G et al . Acta Pediatrica. 2015 Dec 1, 104 (12: 1217-28

NNT: 8 7

Early Hypothermia – Before 3 hours

• Infants cooled within 3 hours of birth appear to have better

neurodevelopmental outcomes compared with infants whose

cooling commences between 3 hours and 6 hours

– No difference in complications

–PDI was significantly higher in the early cooling group

–MDI, CP (no Difference)

Thoresen M, Neonatology. 2013;104:228-233

3

Late hypothermia between 6-24 hours

Azzopardi, Strohm B,PLoS One. 2012;7[6]:e38504.)

TOBY Trial Data

Small effect

size

Cerebral Injury Evolves over Hours to Days

Hypoxia-

ischemiaPrimary Cell-

Death Cytotoxic-

MechanismDelayed -

Neuronal deathSome neurons recover

partially

Apoptosis

Excitotoxic Injury

Inflammation

Oxidative stress

Mitochondrial failure

1

hour

6

hourDays

Timing

≈6 hours

Degree

3°C to 4°CDuration

≈72 hours

ICE WORKS

Seetha Shankaran et al for the NICHD Neonatal Research Network

To determine if longer duration cooling (120 hours), deeper cooling

(32.0°C) or both is superior to cooling at 33.5°C for 72 hours in term

neonates with HIE

72 h

N=185

120 h

N=179

Adj

P-value

PPHN 47 (25%) 60 (34%) 0.13

INO 45 (24%) 60 (34%) 0.07

ECMO* 10 (5%) 12 (7%) 0.52

Arrhythmia 2 (1%) 12 (7%) 0.02

Survivors LOS (d) 22 +15 26 + 34 0.002

NICU mortality 20 (11%) 29 (16%) 0.12

33.5°C

n=191

32.0°C

n=173

Adj

P-value

PPHN 48 (25%) 59 (34%) 0.06

INO 46 (24%) 59 (34%) 0.03

ECMO* 7 (4%) 15 (9%) 0.005

Arrhythmia 5 (3%) 9 (5%) 0.21

Survivors LOS (d) 22 +16 26 + 34 0.21

NICU mortality 22 (12%) 27 (16%) 0.47

Too much ICE for Too long

period is not safe

Cerebral Injury Evolves over Hours to Days

1

hour

6

hourDays

Timing

≈6 hours

Degree

3°C to 4°CDuration

≈72 hours

ICE ++++

cocktails

Cerebral Injury Evolves over Hours to Days

1

hour

6

hourDays

Timing

≈6 hours

Degree

3°C to 4°CDuration

≈72 hours

ICE ++++

Prevent but

Don’t repair

Cocktails: Prevent and Repair

Therapeutic Agents to Augment Cooling

Therapeutic Agent

Adjunct therapy with TH

Stage on the pipeline of development

NOBLE GASES

Xenon

Argon

Clinical Trials completed

Preclinical studies completed

Melatonin New formulation

Pre-clinical studies

Regulatory bodies

Erythropoietin Phase 1 study

Phase Study starting in US

Allopurinol (ALBINO Study)

MgSO4

Horizon 2020 study. 14 European Centers 2016-2020

Mag-COOL Study Feasibility

N- Acetyl Cysteine

Cannabinoids

Noble Gases- Xenon and Argon

200 times cheape than xenon

If used with in one hour

Potent neuroprotective effects:

- NMDA antagonist

- Upregulates survival protenis

- HIF-1-> Epo

- No side effects

- Synthetic Xenon is expensive (30 pound/litre)

Xenon +HT for HIE : TOBY-Xe Trial in UK

– 100 neonates

– 30% Xe started by 12h, inhaled for 24 hours during hypothermia

– Outcomes: neuroimaging at < 15 days (Reduced Thalamic Lactate)

– MRI: FA in PLIC

– MRS: Lactate/NAA ratio

• Results:

– No difference in neuroimaging markers

– Reduction in seizures

Azzopardi et al, 2015, Lancet Neurol; 2013, Arch Dis Child

CoolXenon3 Study combining TH with 18 hours of xenon inhalation in cooled infants with HIE are

pending. (ClinicalTrials.gov NCT02071394)

Melatonin

Augments hypothermic neuroprotection in a perinatal asphyxia model

Brain, 2013 Jan: 136 : 90-105

• Free radical scavengers, antiapoptotic, anti inflammatory, crosses BBB

– Wide range of dosing: 1.5 to 50 mg/kg/dose

• Phase II (N=30) melatonin 10 mg/kg X 5 I +HT

(fewer seizure, less white matter injury, better 6 month outcome)

• Phase II (N=30) dose escalation (0.5-5 mg/kg NG)

• Conclusion

– Natural non toxic, may benefit HIE both as

– Monotherapy and

– Combined with TH (Aly H, 2014, J Perinatology) & (M Weiss, USA)

Journal of Clinical Neonatology | Vol. 4 | Issue 3 | July-September 2015

• 60 babies

• Dose : 2.5 ml/kg/day q 24 h for three doses

(250 mg/kg/dose of 10% MgSO4 )

Conclusions: safe

Long-term survival and ND outcomes remain to be evaluated.

Erythropoietin

Fetal Hypoxia

Epo - receptor upregulated

Astrocytes,

Oligodendrocytes

Progenitor cells

Preventive

+

Repair

Epo safety Records

• Adults

– Hypertension, clotting, polycythemia

– Increase DVT

– Increase death in elderly

• Not reported in newborns

– Swiss study of preterm neuroprotection (n=450)

– PENUT study of preterm neuroprotection (n=940)

– 33 trials of Epo for anemia , 1000-7500 U/Kg per week (n=2693)

ClinicalTrials.gov NCT01378273

EPO + TH trial

• Double blind RCT (N=50 )

• Dose 1000/kg or Saline (Day 1,2,3,4,7)

• MRI Brain (5.2 ± 2.2 days)- after rewarming

–Less Global injury

– at 12 month – NO significant difference

NEAT O Study

Neonatal Erythropoietin And Therapeutic Hypothermia Outcome Study

Wu Y et al. Pediatrics. 2016; 137 (6)

Small

sample

size

Equipoise

• Not enough evidence for safety or efficacy to justify clinical use

Epo studies in neonates with HIE

• 3 ongoing trials (EPO+HT)

– HEAL trials USA (n=500)

– PAEAN trials Australia (n=300)

– NEUREPO Paris (n=100)

ClinicalTrials.gov Identifier: NCT03079167

Abdul Razak, Metanalysis. J. Perinat. Med. 2019

Combination therapy (EPO+MgSO4+TH) for HIE

Open-label pilot study to assess the safety and feasibility

Nonomura, M et allBMC Pediatr 19, 13 (2019) doi:10.1186/s12887-018-1389-z

300 U/kg Epo every other day for 2 weeks,

250 mg/kg magnesium sulphate for 3 days

Therapeutic hypothermia

Feasibility

Resuscitation with Intact Cord- DCC

Anup C Katheria Frontiers in Pediatrics |November 2019 | Volume 7 | Article 473

Placental Transfusion: Breathing + Uterine contraction

Perinatal Asphyxia: Low blood + ECC

STEM CELL – 20 ongoing trial

VISION OF HOW NEUROPROTECTION WILL INVOLVE

A COCKTAIL OF AGENTS

1

Day 3

days

7

Days

Timing

≈6 hours

Degree

3°C to 4°C

Duration

≈72

hours

Room Air

Intact Cord

DCC

Melatonin

MgSO4

Cooling

Noble

Gas

Erythropoietin

PREVENTION -------------------------------------------REPAIR