Erythropoetin in hie,iap neocon, pune,2018 - Dr Karthik Nagesh

1. Erythropoeitin in Neonatal Hypoxic
Ischemic Encephalopathy
• Very Promising !!
Dr.N Karthik Nagesh MD,FRCPCH ( UK), FNNF
Chairman & HOD –Neonatology,Manipal Hospitals, Bangalore
Professor of Neonatology, Manipal University

2. EPO in Neonatal HIE
• How it works
• Evidence
• Possible Modes of Therapy
• Future Prospects

3. Neonatal HIE
Birth asphyxia contributes to a significantly higher burden of
neonatal mortality and morbidity globally, more so in developing
countries.
• Four million newborns each year
• Estimated one million deaths and 42 million disability-
adjusted life years
• Also leads to devastating neurological consequences
such as cerebral palsy, epilepsy, and mental
retardation.

4. • Therapeutic hypothermia (TH) is now standard of care for
infants with moderate to severe HIE
• Widespread clinical use of TH over the last decade-the
prognosis of moderate HIE has significantly improved.
• But TH has not definitively changed outcomes in severe
HIE.
Therapeutic hypothermia (TH) in HIE

5. TH – Limitations
• Meta-analysis of trials evaluating TH for neonatal
encephalopathy in low-and middle-income countries (LMIC) also
showed that TH was not associated with a statistically significant
reduction in neonatal mortality
Major contributing factors;
• Lack of tertiary care facilities
• Inadequate neonatal transport
• High rate of neonatal sepsis/inflammation
• Growth retardation
• Suggesting a chronic perinatal insult in these infants in LMIC.
‘
• Alternative ‘low cost cooling methods as well as ‘adjuncts’ and
affordable treatment options such as Epo/magnesium are being
evaluated

6. ACCUMULATION OF K,
EXCITATORY A A, e.g.-
GLUTAMATE
DELAYED NEURONAL
DEATH(NMDA Channel)
CELL NECROSIS
APOPTOSIS
ACTIVATION OF
LIPASES,
CYTOKINES
FREE RADICALS –
O, OH-
, HO,
SUPEROXIDE
REPERFUSION
HYPOXIC ISCHEMIC BRAIN INJURY
PATHOPHYSIOLOGY
HYPOXIA
ATP  GLUCOSE
DELIVERY
ISCHEMIA
FAILURE OF ION
PUMPS
(Na, K, ATPase)
INTRACELLULAR
ACCUMULATION OF
Na,Ca,Mg,Cl.
+
IMMEDIATE
NEUORONAL DEATH
ANAEROBIC
GLYCOSIS
LACTIC ACIDOSIS
 ACIDOSIS

9. Reducing Brain Damage in HIE
The recognition of mechanisms of brain damage has opened up
new research into neuro-protective therapies
• To attenuate brain damage
• To promote cell repair and regeneration in the developmentally
disorganized brain long after the perinatal insult.
• These alternative modalities may be especially important in mild
HIE in areas where there is limited access to expensive
hypothermia equipment and services.

10. HYPOTHERMIA

11. Therapies that are beneficial and agents that hold promise for
neuroprotection both for use ‘either alone’ or as ‘adjuncts to TH’.
• Endogenous pathway modifiers such as erythropoietin and
analogues, melatonin, and remote ischemic post conditioning.
• Exogenous therapies such as argon and xenon, allopurinol,
monosialogangliosides, and magnesium sulfate continue to be
investigated.
• Stem cells have therapeutic potential

12. Neuroprotective Strategies Being Evaluated For Use In
Management of HIE
 Decreasing oxidative stress
 Antagonizing excitatory
neurotransmitter release
 Receptor blockade
 Anti-inflammatory effects
 Immunomodulation
 By decreasing apoptosis
• Primarily to mitigate
devastating effects from
‘secondary energy failure’ on
the brain.
• Therapies that are applied in
experimental and animal
models of HIE generally
work on ‘slowing the
pathophysiology’

13. Additional Neuro-Protection in Neonatal HIE
• There is ongoing search for additional treatments.
• Ideal neuroprotective treatments should be safe,
readily available, inexpensive, and effective when
given after an injury occurs.
• The evidence for Epo neuroprotection is most
promising to date, with positive data from both
preclinical and clinical trials.

14. HIE – Newer Treatment Strategies

16. EPO and its effects
• Erythopoietin (Epo) is an endogenous protein, synthesized in the fetal liver
• Epo receptors (EpoR) are widely expressed throughout the central
nervous system in several cell types including progenitor cells, astrocytes,
oligodendrocytes, and microglia
• Neurons and oligodendrocytes have a greater risk of apoptotic cell
death when Hypoxic
• Epo and EpoR are upregulated following hypoxic ischemic injury
• In Severe HIE in infants – the Hypoxia stimulates Erythropoietin
production by the kidneys
• Epo has an anti-oxidant and anti-inflammatory effect.
• It reduces Apoptotic and Excitotoxic cell injury

18. How Epo Helps in Neuroprotection

24. Erythropoeitin- Epo Clinical Use
• Approved for many years
• Safety proven in neonates
• Easily available
• Inexpensive

25. Clinical Trials Of Erythropoietin In Neonatal Populations
• In the past 8 years, many clinical trials to
evaluate the safety and efficacy of Epo in
various neonatal conditions have emerged.
• Pharmacokinetic and safety studies have shown
that Epo dosed from 500 to 3000 U/kg is safe in
preterm and term neonates.

27. Clinical Trials of EPO in HIE
Phase I trial evaluating effective dose and safety
demonstrated that a moderately high dose of 1000 U/kg
achieved adequate levels (based on animal studies) and was
tolerated Wu, Y.W. et al; Pediatrics 2012
In Phase II double-blinded, placebo-controlled trials in infants
undergoing TH for HIE,Multiple doses of Epo (1000 U/kg)
resulted in less MRI brain injury and potential for improved
short-term motor outcomes Wu, Y.W.; et al Pediatrics 2016,
•
• A Phase III trial evaluating the effect of Epo along-with TH
on the combined outcome of death or neurodevelopmental
disability is currently underway Juul, S.E et al; Neonatology 2018
•

29. • This study was the first to describe
neurodevelopmental outcomes in infants who
received high doses of Epo and hypothermia
during the neonatal period.
• The findings suggest that future studies are
warranted to assess the efficacy of this new
potential neuroprotective therapy.

30. CLINICAL TRIALS – EPO IN HIE
• Neonatal Erythropoietin And Therapeutic Hypothermia
Outcomes in Newborn Brain Injury (NEATO) study enrolled 50
subjects Wu Yw et al Pediatrics 2016
• With moderate or severe HIE and randomized them to Epo or
placebo in the setting of therapeutic hypothermia.
• Despite no differences in enrollment characteristics, severity of
injury on early MRI was significantly lower in infants treated with
Epo
• Neurodevelopment at 1 year of age was improved in the Epo-
treated group.

31. High doses of Epo given with hypothermia for
hypoxic-ischemic encephalopathy may result in
less MRI brain injury and improved 1-year motor
function.
www.aappublications.org by Volume 137, number 6, June
2016:e20160191

32. EPO Clinical Trials – HIE
• Epo vs Supportive care in infants with moderate-to-
severe HIE. Zhu et al, Pediatrics,2009
• Epo was dosed at either 300 or 500 U/ kg and given
immediately after injury and repeated every other
day for 2 weeks.
• The authors demonstrated a decreased incidence of
moderate-to-severe disability or death at 18 months
of age in infants given either of the 2 doses of Epo

33. EPO vs Placebo in Neonatal HIE
• Randomized 100 neonates born at term with mod. or severe HIE
• Epo or Placebo Given Intravenously on alternate days for a total
of 5 doses,(500 IU/Kg) with the first dose given by 6 hours of
age. No hypothermia was used.
• Death or moderate or severe disability occurred in 40% of
neonates in the treatment group compared with 70% in the
placebo group (risk ratio 0.57; 95% CI 0.38-0.85; P = .003).
• The risk of CP and seizure burden were lower among survivors in
the treatment group, P = .04. Malla R et al, J Perinatol 2017;37:596–601.

34. Epo Analogue – Darbe
• Darbepoietin (Darbe)- long acting erythropoietin analogue that
offers the additional benefit of once weekly administration.
• Two large multicenter randomized controlled trial evaluating
use of darbe in mild HIE currently underway (MEND study).
The Darbe Administration in Newborns Undergoing Cooling for
Encephalopathy (DANCE)
• It could be used potentially as a monotherapy in low-income
countries in which therapeutic hypothermia has not been
shown to be effective

35. HEAL Trial will evaluate whether high- dose Epo
reduces the combined outcome of death or
neurodevelopmental disability when given in
conjunction with hypothermia to newborns with
moderate/severe HIE.

36. EPO in Neonatal HIE
Summary of Clinical Trials
• Heterogenous trials
• With TH or Alone
• Different short and long term outcomes assesed
• Helps ‘Alone’ in HIE
• Helps as ‘Adjunct’ to TH in HIE
• Proven Neuroprotective Role
• No clear guidelines on:-
* When to administer?
* Dose / Route in HIE ?
* Duration ?

37. Well Proven Role of Epo

38. Way Ahead – Epo in HIE
Multicentre RCT in LMIC is needed to address
these Questions;
• In Acute Phase as well as for Delayed Efficacy
• With Epo ‘either Alone’
• Or as ‘Adjunct Along With TH’