Dr. P. K. Rajiv MBBS DCH MD Fellowship in Neonatology( australia ) Specialist Neonatologist &Pediatrician Department of Pediatrics Prime Hospital Dubai, UAE

.

Formerly:

Professor & HOD

Department of Neonatology

Amrita Institute of Medical Sciences, Kochi, Kerala, India

• Problem Statement, Definition • Pathophysiology • Latest trends in Management • Total body cooling • Current trends inNeuroprotection • Prognosis

OBJECTIVES

(

The World Health Organization (WHO) estimates that globally, between four and nine million newborns suffer birth asphyxia each year. Of those, an estimated 1.2 million die and almost the same number develop severe consequences. The WHO also estimates that globally, 29%of neonatal deaths are caused by birth asphyxia

As many as 80%of infants who survive severe hypoxic-ischemic encephalopathy develop serious complications, 10-

20% develop moderately serious disabilities, and as many as 10%are healthy

More than a million children who survive birth asphyxia develop problems such as cerebral palsy, mental retardation,

learning difficulties, and other disabilities

• Severe asphyxia: Cerebral Palsy, Mental retardation, and • Epilepsy

• Mild-Moderate asphyxia: Cognitive and behavioural alterations, • Hyperactivity, Autism, Attention deficits in children and

• adolescents, Low IQ score, Schizophrenia and Development • of psychotic disorders in adulthood

What is asphyxia ?

AAP/ACOG:

Essential criteria Suggestive Criteria

Metabolic Acidosis (Umbilical cord arterial blood PH<7, BE >12

Sentinel or Hypoxic event before or after onset of labour

Early Onset Moderate – Severe Encephalopathy in >34 weeks

Abrupt Change in Fetal Heart Rate

CP of spastic Quadriplegic or Dyskinetic

APGAR score <3 at ≥ 5min

Excluding other identifiable causes Multiorgan involvement <72 hours

Early imaging showing acute non-focal cerebral abnormality

PATHOPHYSIOLOGY

Diving reflex Increased blood

flow to Brain,

Heart, Adrenals

Pathophysiology

© MW Ferriero DM: Neonatal brain injury, N Engl J Med 351:1985–1995, 2004.

Cerebral Blood Flow Energy Metabolism - Decrease in ATP

Glutamate release

Conceptual Model of HIE

Free Radicals

Inflammation

Intracellular calcium

Genetics

Membrane Depolarization

Regeneration

Management OF HIE

Clinicalparametres Stage 1 (mild)

Stage2 (moderate)

Stage3 (severe)

Level of consciousness Alert Lethargy Coma

Seizures No Common Decerebration

Sucking Active Weak Absent

Moro’s Exaggerated Incomplete Absent

Grasping Normal/exaggerated

Exaggerated Reduced/absent

Doll’s eye/ oculocephalicreflex

Normal Over-reactive Reduced/absent

Muscletone Normal Hypotonia Flaccidity

Myoclonus Present Present Absent

Tendon reflexes Normal/increased

Increased Depressed/absent

Duration < D1 D1-D5 > 5D

(Data from Sarnat & Sarnat (relevant in term newborns only)

Neurological monitoring

EEG/aEEG

EEG / aEEG:

• To prognosticate neurological outcome

(95% NPV to diagnose adverse neurological outcome)

• To diagnose non convulsive seizures

.

SEIZURES

sudden increase in voltage,

lnarrow bandaEEG& period

of suppression)

NIRS

NEUROPROTECTION

Sensitization

(Prenatal

factors)

Prenatal

Insult

Brain

lesions

Earl events

Brain lesion

Late events

Post-lesion

plasticity

Time frame of potential strategies for neuroprotection

Prevention Pharmalogical

blockade Growth Factors

HIE :PROPOSED INTERVENTIONS

Energy

Metabolism

Excitatory

Glutamate

Calcium

Mediated

effects

Nitric Oxide

Free Radicals

Inflammatory

Mediators

Neuroprotection after Hypoxic Event

Therapeutic

Window:

Hypothermia

Other

Neuroprotection strategy in clinical use

Therapeutic hypothermia

• Decrease energy consumption • Decrease accumulation of extracellular

glutamate • Decrease generation of reactive oxygen &

nitrogen • Inhibits inflammation

Therapeutic Hypothermia

ELIGIBILITY

Gestational Age ≥36 weeks AND

Time line ≤6 hours of age AND

Evidence of Asphyxia:

Apgar score ≤5 at 10 minutes after birth OR

Continued need for PPV / Chest Compressions at 10 min after birth

PH ≤7.00 or base deficit ≥16 mmol/L in an umbilical cord blood sample or any blood sample obtained within the first hour after birth AND

Moderate or severe encephalopathy on clinical examination

Additionally in

COOL CAP TRIAL: Moderately or severely abnormal background of at least 20 min

duration or seizure activity on aEEG after 1 hour of age

TOBY TRIAL: Abnormal background activity of at least 30 min

duration or seizures on aEEG

Methods of cooling

Selective head cooling

Whole body cooling

• 11RCT, N=1505

• TH decreased the combined outcome of death or major

neurodevelopmental disability at 18 months of age (46% vs.

61%) (RR 0.75, NNT-7)

• Decreased mortality with TH (25 vs 34%, RR 0.75, NNT-11)

• Decreases neurodevelopmental disability in surviving infants

(26% vs 39%, NNT-8)

Therapeutic Hypothermia for Moderate

to Severe HIE in Term & Late Preterm:

Cochrane Review 2013

Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG.Cooling for newborns with hypoxic ischaemic

encephalopathy. Cochrane Database Syst Rev. 2013;(1):CD003311

• Cochrane: Significant adverse effects of TH are

Sinus bradycardia and thrombocytopenia

• Other reported side effects: fat necrosis, DIC, and rarely pulmonary hypertension

• No Increase: in major cardiac arrhythmia and

hypotension or in the need for inotropic agents.

Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG.Cooling for newborns with hypoxic ischaemic

encephalopathy. Cochrane Database Syst Rev. 2013;(1):CD003311

Long term Outcomes - NICHD trial

• At ages of 6–7 years

• The primary outcome of death or IQ <70: low in TH (47% vs 62%) • but no longer significant (RR in TH group 0.78, 95% CI 0.61–1.01) • Death rate: Significantly lower in TH group (28% vs 44%, P = .04) • Rate of death or severe disability: (41% vs 60%, P = .03)

• No significant difference in the rates of moderate or severe disability • (35% vs 38%, P = .87) or CP (17% vs 29%, P = .14) • • TH increases survival without increasing rates of major disability,

an IQ score below 70, or CP in surviving children

Shankaran S, Pappas A, McDonald SA, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N

Engl J Med. 2012;366:2085-2092.

Duration & Depth of Cooling:

• In 2014, NICHD Trial: Compared cooling for 120 hrs, or to 32°C Vs cooling at 33.5°C for 72 hrs • Adjusted RR for NICU deaths of 1.37 (95% CI: 0.92 to 2.04) for 120 hrs group Vs. 72 hrs group (17% vs 14%) • Trial was stopped early for safety

• On follow up at 18months age, that infants who were cooled for • 120 hrs at 32°C had lowest disability rates but highest mortality rates

• Current evidence suggests that cooling for >72 hours is not beneficial. • Currently No evidence to cool below target temperature of 33.5°C (33°C-34°C)

Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, Tyson JE, et al. Effect of depth and duration of cooling on deaths in the

NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA. 2014 Dec 24-31;312(24):2629-39.

Therapeutic Hypothermia For Mild HIE:

• To examine effect of TH on composite outcome of death, moderate or severe disability at 18 months or more after mild HIE

• Meta analysis, N=117, 5 Trials, mild HIE but inadvertently recruited (2 whole-body cooling and 3 selective head cooling) • Adverse outcomes in 19.6% of TH Vs 19.7% of routine care babies

(RR-1.11 (95% CIs 0.55 - 2.25)) • Insufficient evidence to recommend routine TH for mild HIE and significant benefits or harm cannot be excluded

• Adverse neurological outcomes at 18 months or more, occur in 20% of babies with mild HIE

Kariholu U, Montaldo P, Markati T, et al Therapeutic hypothermia for mild neonatal encephalopathy: a systematic review and

meta-analysis Archives of Disease in Childhood - Fetal and Neonatal Edition Published Online First: 19 December 2018.

TH in Low-middle Income Countries

• Meta analysis, 7 trials, N=567 infants • Most study infants had mild (15%) or moderate

encephalopathy (48%) and did not receive invasive ventilation (88%)

• Cooling devices included water circulating cooling caps, frozen gel packs, ice, water bottles, and phase-changing material

• No statistically significant reduction in neonatal mortality was seen with cooling (risk ratio: 0.74, 95% confidence intervals: 0.44 to 1.25)

• Data on other neonatal morbidities and long-term neurological

outcomes were insufficient

Pauliah SS, Shankaran S, Wade A, Cady EB, Thayyil S (2013) Therapeutic Hypothermia for Neonatal Encephalopathy in Low- and Middle

Income Countries: A Systematic Review and Meta-Analysis. PLoS ONE 8(3): e58834. doi:10.1371/journal.pone.0058834

Additional neuroprotective agents

Despite treatment with therapeutic hypothermia, almost 50% of infants with neonatal encephalopathy still have adverse outcomes. Additional treatments are required to maximize neuroprotection

Promising therapies in management of HIE

• EPO – for normal brain development, Source – Astrocytes mainly

• Receptor (EpoR) – present on Astrocytes, Neurons,

Oligodendroglia, microglia, endothelial cells

• Events: Hypoxia HIF EPO

• Epo (endogenous or exogenous) binds to cell-surface

EpoR: Decreases local inflammation and apoptosis and

enhancing neurogenesis, angiogenesis, and erythropoiesis

• Combined effects decrease acute injury and enhance repair

Erythropoietin

Systematic review on EPO in HIE:

• 9 Studies, Six studies – without TH, 3 studies - with TH

• Started with in 24 h of age except in Zhu et al. (in <48 h age)

• Duration: Total of 5–7 doses either on alternate days or on daily basis except in three studies (El Shimi et al: only single dose; Avasiloaiei et al: 3 doses; Wang et al: 7–14 doses of EPO)

• Dose in studies - wide range: 200 - 2500 U/kg/dose (I.V./S.C)

• Wu et al:1000 U/kg/dose provides optimal neuroprotection

• No serious adverse events even with highest dose (2500 U/kg/dose)

Bhawan Deep Garg, Deepak Sharma & Anju Bansal (2017): Systematic review seeking erythropoietin role for

neuroprotection in neonates with Hypoxic ischemic encephalopathy: presently where do we stand, The Journal of

Maternal-Fetal & Neonatal Medicine, DOI: 10.1080/14767058.2017.1366982

Reduction in Death and disability, Breakthrough seizures Better long-term neuro-developmental outcome

Improvement in EEG Reduction in risk of CP Reduction in number of neonates on anticonvulsant

treatment at assessment Reduction in Abnormal brain MRI, Better NBNA score,

Reduction in brain injury

Conclusion: EPO treatment has neuroprotective effects

against moderate/severe HIE and improves long-term behavioral neurological developments in neonates

Needs more studies for recommendation

Bhawan Deep Garg, Deepak Sharma & Anju Bansal (2017): Systematic review seeking erythropoietin role for

neuroprotection in neonates with Hypoxic ischemic encephalopathy: presently where do we stand, The Journal of

Maternal-Fetal & Neonatal Medicine, DOI: 10.1080/14767058.2017.1366982

Darbepoetin: (Darbe)

• EPO analog, lower receptor binding, longer half life

• Effective, Less frequent dosing than EPO

• DANCE Trial (Darbe Administration in Newborns

Undergoing Cooling for Encephalopathy): Measured Pharmacokinetics of 2 and 10 g/kg doses of

Darbe and demonstrated short-term safety • MEND Trial (Mild Encephalopathyin the Newborn Treated

with Darbepoetin): Ongoing, Multicenter RCT, 1 dose within 24hrs

Xenon

• Noble gas crosses BBB

• NMDA Antagonist – prevents post-synaptic

binding of glutamate, which is an excitatory neurotransmitter

• Decreases neuronal apoptosis

• Preclinical studies – significant benefit

• CoolXenon 1Trail –feasibility trail in 12 infants –

no adverse events

TOBY-XE trail: • TH Vs 30%Xe+TH (n = 46 vs 46)

• Outcome: MRI/MRS-based: preserved fractional

anisotropy (FA) in the posterior limb of the internal capsule determined within 15 days of birth and MRS assessment of thalamic lactate to NAA ratios

• No significant difference • Ongoing Trials: CoolXenon 2, 3 • Limitations of Xe: Cost, need for recycling system,

decreasing available Fio2

Azzopardi D, Robertson NJ, Bainbridge A, Cady E, Charles-Edwards G, Deierl A, et al. Moderate hypothermia within 6 h

of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBYXe): a proof-of-concept,

open-label, randomised controlled trial. Lancet Neurol 2016;15:145-53.

Argon:

• Similar to Xenon, Noble gas crosses BBB

• NMDA Antagonist – Decreases neuronal apoptosis

• Preclinical studies – significant benefit

• Cardiovascular stability in Therapeutic Hypothermia

• Cheaper than Xenon

Melatonin: N-acetyl-5-methoxytryptamine

• Neurohormone, tryptophan derived, secreted by pineal gland

• Strong Antioxidant: stimulating several antioxidative enzymes including glutathione, glutathione reductase, peroxidase, and superoxide dismutase

• Also: Anti-inflammatory, Antiapoptotic properties

• In animal models (piglets) - beneficial

• Fulia et al: Reduced the serum malondialdehyde, a lipid peroxidation product, and nitrite/nitrate levels suggesting a role in reducing oxidative damage

Fulia F, Gitto E, Cuzzocrea S, et al. Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated

newborns: reduction by melatonin. J Pineal Res. 2001;31:343-349.

• Aly et al: TH Vs TH+Melatonin (N= 15 vs 15)

• 10mg/kg daily x 5days, Enteral route

• Decreased seizures, white matter abnormalities on MRI after 2

weeks, improved survival without neurological abnormalities at 6 months of age (P<0.001)

• Melatonin: potential agent for antenatal therapy

• Appears safe, crosses the placenta and crosses the blood–brain barrier

• Can be administered to pregnant mothers with at-risk fetuses

• Further research - ongoing

Aly H, Elmahdy H, El-Dib M, et al. Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled

pilot study. J Perinatol. 2015;35:186-191

Topiramate

• Topiramate blocks the voltage-dependent Na and Ca channels

• Inhibits the excitatory glutamate pathway while enhancing the inhibitory effects of GABA

• Reducing calcium overload in the ischemic cells and by increase the seizure threshold

• Filippi et al, 2010: TH vs TH+Topiramate (n= 27 vs 27)

• Oral topiramate, once a day 3 consecutive days, at 2 different doses (8.2 to 26.0 mg/kg/day)

• No differences in Outcomes But found to be safe

Filippi, L.; Poggi, C.; la Marca, G.; Furlanetto, S.; Fiorini, P.; Cavallaro, G.; Plantulli, A.; Donzelli, G.; Guerrini, R.

Oral topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia: A safety study.

J. Pediatr. 2010, 157, 361–366

• NeoNATI Trial: Feasibility Trail on Topiramate in HIE

• Multicenter RCT. TH vs TH+Topiramate (n= 23 vs 21)

• Topiramate dose: 10mg/kg once a day x first 3 days of life

• No statistically or clinically significant differences were observed for safety, primary (mortality & severe neurological disability) or secondary outcomes

• Reduction in prevalence of epilepsy in TH+Topiramate Group

• Conclusions: Topirmate in newborns with HIE is safe but does not reduce the combined frequency of mortality and severe neurological disability

Filippi, L.; Fiorini, P.; Catarzi, S.; Berti, E.; Padrini, L.; Landucci, E.; Donzelli, G.; Bartalena, L.; Fiorentini, E.; Boldrini, A.; et

al. Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia

(NeoNATI): A feasibility study. J. Matern. Fetal Neonatal. Med. 2018, 31, 973–980.

• Activation of Xanthine oxidase Decreases Oxidant injury by free radicals super oxides

• Cochrane review in 2012: No significant difference in the

risk of death or a composite of death or severe

neurodevelopmental disability

• Follow-up of two earlier performed RCTs at 4–8 year: Neuroprotective effect of neonatal allopurinol treatment in the subset of moderately asphyxiated infants

Allopurinol:

Chaudhari, T.; McGuire,W. Allopurinol for preventing mortality and morbidity in newborn infants with hypoxic-

ischaemic encephalopathy. Cochrane Database Syst. Rev. 2012, CD006817

Kaandorp, J.J.; van Bel, F.; Veen, S.; Derks, J.B.; Groenendaal, F.; Rijken, M.; Roze, E.; Venema, M.M.; Rademaker,

C.M.; Bos, A.F.; et al. Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: Follow-up

of two randomised controlled trials. Arch. Dis. Child. Fetal Neonatal. Ed. 2012, 97, F162–F166

AUTOLOGUS UC BLOOD– STEM CELL

• Different cells: Neural stem cells, embryonic stem cells,

umbilical cord blood (UCB) stem cells, bone marrow–derived

mesenchymal stem cells (MSCs), and inducible pluripotent stem cells

• In recently, focus on to MSC, especially UCB-MSCs

• MSCs do not engraft but rather respond to signals of local injury by secreting trophic factors

• Increasing progenitor cell proliferation

• Increased survival of neurons and neuronal stem cells • Reduction of inflammation

• Stimulate axonal sprouting, Proliferation of oligodendrocyte precursors and promote mature oligodendrocytes

Stem Cells:

• 2 doses given 3 and 10 days after injury provides better neuroprotection

• Park et al: Combined treatment of human UCB derived

MSC transplantation and hypothermia in a severe neonatal hypoxia–ischemia

• Showed improvement in infarction, behavioral testing, and

reduction in inflammation, which was better than either

therapy alone

Park WS, Sung SI, Ahn SY, Yoo HS, Sung DK, Im GH, et al. Hypothermia augments neuroprotective activity of

mesenchymal stem cells for neonatal hypoxic-ischemic encephalopathy. PLoS ONE 2015;10:e0120893.

• Cotton et al: n=23, Safety and feasibility trail

• IV administration of noncryo preserved, autologous UCB

cells

• No significant adverse reactions, cardiopulmonary

compromise, or infections with the transfusion of up to 4 doses of 1-5 × 107 cells per dose

• At 1 year with Bayley scores >85: in UCB recipient infants 74% Vs 41% in the concurrent cooled infants

• Needs further research

Cotten CM, Murtha AP, Goldberg RN, Grotegut CA, Smith PB, Goldstein RF, et al. Feasibility of autologous cord blood

cells for infants with hypoxic-ischemic encephalopathy. J Pediatr 2014;164:973-9, e1.

Other Agents – Preclinical Trials

Options Rationale N-Acetyl Cysteine Antioxidant, Glutathione Precursor

PolyPhenols (Resveratrol, Curcumin) –

Natural molecules from vegetables, fruits

etc

Antioxidant, Anti-inflammatory,

Antiapoptotic

Lithium Antiapoptotic, Inhibits NMDA

receptor excitotoxicity

Cannabinoids Decrease Glutamate excitotoxicity

Levetiracetam Inhibit AMPA and NMDA mediated excitation

Summary of Neurprotective Interventions Besides Cooling: Recent Evidence

PROGNOSIS OF HIE

Prognosis in HIE

Usually by a neurological examination

TheSarnatandSarnatstages predict long-term outcome, but are often determined well after birth (Sarnat&SarnatArch Neurol.1976)

How useful is an early neurologic evaluation? Which parts of the neurologic evaluation are useful?

Failure to establish respiration by 5 minutes Apgar3 or less in 5mts Onset of Seizure in 12 hrs Refractory convulsion Stage III HIE Inability to establish oral feed by 1 wk Abnormal EEG & failure to normalize by 7 days of life Abnormal CT, MRI, MR spectroscopy in neonatal period

Amplitude Integrated EEG

Good prognostic indicator

immediately after birth on

future neurodevelopment

status

Assess the background

activity of a compressed

EEG

PROTON MRS –Evaluation of cerebral energy metabolism

Provide important prognostic data during the first week Reduction inNacetylaspartateand elevation of Lactate in the thalamus /basal ganglia(increase Lac/NAA ratio)correlate with adverse outcome. Earliest indicator of neurological handicap

MR SPECTROSCOPY: • MRS): provides additional prognostic information

• N-acetyl aspartate (NAA): found in neurons, reduction in NAA peak is thought to reflect neuronal injury or loss

• Choline: cell membrane component and also present in the neurotransmitter acetylcholine

• Lactate: after asphyxia and anaerobic glycolysis

• Ratios of NAA/choline or NAA/lactate: provide prognostic information - extent and severity of brain injury.

Normal neonatal

proton spectra

The spectrum reveals: 1) a smallmyoinositolpeak,

2) a largecholinepeak, 3) Two smallcreatine

/phosphocreatinepeaks, 4) a medium-sized NAA peak.

Neonate with

basal nuclei pattern of injury.

Both spectra show some lactate

elevation at 1.31ppm.

The spectrum from the basal

nucleivoxel(A), however, shows a

relatively smaller elevation of

lactate (filled arrow) than the

spectrum (open arrow) from the

watershedvoxel(B).

Neonate with

watershed

pattern of injury.

RESISTIVE INDEX(RI)

Doppler assessment helps in measurement of cerebral blood flood velocity (cerebralhemodyanamics)

The cerebral blood flow velocities initially increase due tohyperperfusionand later decrease in those who develop HIE. RI< 0.50 or >0.90in the cerebral blood vessels is associated with immediate and long term poor outcome, RI> 1.0would be associated with later brain death.

If the RI in a baby with encephalopathy is abnormal on day 1, this suggests that an insult occurred in the 1-2 days preceding birth

Role of MRI

Useful in prognosis

Imaging biomarkers of HIE

DWI detect lesion earlier than T1-T2 weighted images.

Sites of abnormality

Basal ganglia and thalami Internal capsule Cortex Subcorticalwhite matter Medial temporal lobe Brainstem Increased metabolic rate Actively myelinating Increased glutamate receptors

NORMALPLIC

NORMAL POSTERIOR

LIMB OF INTERNAL

CAPSULE

NORMAL

BASAL

GANGLIA

AND THALAMUS

BGT

Abnormal signal intensity within

the PLIC (arrow) predicts

abnormal motor outcome

Sensitivity= 0.9 Specificity = 1.0 *

Severe; widespread

with abnormal PLIC

Major Aspects of MRI in the Diagnosis of HIE in the Term Infant

Neuropathological patterns & clinical features

Mild; Focal with

normal PLIC

Long term Outcomes: TOBY Trial

• At 6–7 yrs of age

• IQ of ≥85 52% vs 39% (RR 1.31, P = .04) • • Death rates were similar (29% vs 30%)

• In survivors: TH Vs Control

• Normal neurologic outcomes 45% vs 28%; RR -1.60

• Risk of CP: 21% vs 36%

• Moderate or severe disability: 22% vs 37%

Azzopardi D, Strohm B, Marlow N, et al. Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J

Med. 2014;371:140-149