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Dr. Anand Gangadharan
Initial management, promoting adequate
• Oxygenation
• Ventilation
• Circulation
• Correction of metabolic derangements
• Continous BP monitoring – low cardiac output sec. to
myocardial ischemia
• Respiratory compromise sec. to – ischemic effects on lungs,
impairment of CNS, frequent exposure to MSAF & pulmonary
hypertension.
• Hypocarbia sec. to respiratory compensation of metabolic acidosis.
– compromise cerebral autoregulation & exacerbate brain injury.
• Hence, adequate management of respiratory status & blood
chemistry.
• Fluid & electrolyte imbalance – due to cerebral edema &
secondary SIADH.
• Hypoxia – AKI – oliguria, anuria, fluid retention & electrolyte
abnormalities ( Hyponatremia)
• Hyponatremia – Seizures – exacerbate brain injury & worsen
cerebral edema.
• Fluid & electrolyte management – critical.
• Glucose homeostasis – often disrupted.
• Hypoglycemia – exacerbate brain injury & induce seizures.
• Prompt treatment of acute symptomatic seziures.
• Liver injury & DIC.
• DIC with bleeding – immediate treatment.
• Additional vitamin K – production of vitamin K dependant
clotting factors
• Abnormal renal & hepatic function – metabolism & clearance
of medications (phenobarbitone, Gentamicin & Furosemide)
Hypothermia therapy
• Only proven neuroprotective therapy for HIE
1. Decreases cellular metabolism by 5-8% / deg C
2. Attenuates inflammatory reaction
3. Stabilizes BBB
4. Reduces glutamate & O2 free radicals.
5. Anti-epileptic effects
• Beneficial effect most pronounced – applied before the onset of sec.
energy failure (ie, within 6 hours of birth)
• Applying hypothermia within 6 hours of birth to maintain the core
body temp. at 33.5+/- 0.5 degC for 72 hours followed by slow
rewarming at a rate of 0.5 degC/h to normothermia, in numerous RCT
to improve outcomes in neonates with mod. to severe HIE.
• Alteration in pharmacokinetics – enzyme dependant metabolism
(phenobarbitone, Fentanyl, Midazolam, Phenytoin, Corticosteroids &
Vecuronium)
- enzyme facilitated conjugation (hepatic glucuronidation – Morphine)
• In human studies, no association of NEC with hypothermia alone or
with initiation of enteral feeding.
• SCFN – back & shoulders, 2.8%
• Studies evaluation duration (120h vs 72 hours), depth (32 deg C vs
33.5 deg C) & initiation (6 & 24 hours) – no benefit but potential harm.
• Passive cooling before active cooling if there is any delay, active
cooling during transport is preferred.
• Centres offering TH, should have
o cEEG or aEEG
o Pediatric neurologist
o MRI with neuroradiology interpretation
o Ancillary services – PT, ST, high risk follow up OPD
Medication for sedation & prevention of shivering
• Morphine – not evidence based, not ideal due to side effect
profile – respiratory depression, urinary retention,
constipation
• Dexmedetomidine & Clonidine ( alpha2 adrenergic receptor
agonists), specifically prevent shivering without supressing
respiration.
• Dexmedetomidine – reduces inflammation, neuroprotection (
animal studies)
Outcomes of TH
• Prior to TH – mortality in mod. to sev. HIE >60% & 100% in
sev. HIE.
• Cochrane meta analysis – 1505 term & late preterm infants
with moderate to severe HIE from 11 randomized controlled
trials & concluded that TH results in fewer deaths.
Cool cap trial
NICHD
TOBY
HELIX
Helix trial
• Largest neonatal cooling trial reported till date
• No difference between the RCT arms for the primary
outcome.
• Mortality at 18 months was increased in TH group.
• Neonates who have, quick clinical recovery, a normal EEG
background pattern, a normal MRI, & a normal neurological
examination at 7 to 10 days of age often have a favorable
long-term outcome.
National Neonatology Forum, India
Position Statement and Guidelines
For Use of Therapeutic Hypothermia
to treat Neonatal Hypoxic Ischemic
Encephalopathy In India
October 2021
• 1. TH likely to decrease death or severe disability and cerebral
palsy at 18-24 months even in LMICs as compared to HICs.
• 2. There is significant heterogeneity in the studies from LMICs
compared to HICs which reported mortality prior to discharge
following TH in neonates with HIE. The pooled estimates for
mortality prior to discharge showed a significant benefit in
favour of TH (RR 0.77, 95%CI 0.62-0.94) in HICs. In the studies
from LMICs there was uncertainty (RR: 0.74; 0.53 to 1.02); a
possible reason could be the lack of certainty of the
encephalopathy being due to an asphyxial insult.
3. Mortality before discharge when analyzed for infants with moderate-
severe HIE with cord pH <7.0 showed no significant heterogeneity in
studies from HICs and LMICs and significant benefit in favour of TH in
both subsets (HICRR 0.69,0.54-0.88; LMIC- RR 0.58, 0.43-0.79).
However, in studies that reported cord pH>7.0 or did not report cord
pH, there was considerable heterogeneity and no benefit in survival
prior to discharge.
4. In neonates with hypothermia at admission and unclear evidence of
severe intrapartum asphyxia (cord pH>7.0 or cord pH not available -
more often seen amongst outborn neonates in LMICs) there is
uncertainty of the benefit from TH (ranging from benefit to harm).
5. As the risk of death increases with severe encephalopathy,
need for invasive ventilation, and inotropic support,
availability of optimum neonatal intensive care facilities is
essential if TH is to be offered at a health facility.
Which neonates should be offered TH?
• It is recommended that TH should be offered to neonates with HIE
with gestational age > 36 weeks, <6 hrs of age of life and with
admission temperature 36-37.4 degC, IF they fulfil all of the
following criteria:
1. pH<7 or BE >-16 on cord or arterial blood gas done within 1 h of life AND
• Apgar score < 5 at 10 minutes or at least 10 min of positive pressure ventilation AND
• history of acute perinatal event (such as but not limited to placental abruption,
uterine rupture, cord prolapse)
2. Evidence of moderate or severe encephalopathy
• During preparation for cooling if the neonate’s encephalopathy has improved
(becomes mild or normal), therapeutic hypothermia may be deferred and
neonate observed closely and offered continued supportive care
• Prior to initiating TH it must be ensured that parents are provided sufficient
information about the benefits and harms of cooling, the details of the
procedure and outcomes.
• A written consent must be obtained from parents/legal guardians.
• It must be ensured that the neonate’s cardio-respiratory status is stable prior
to initiating cooling.
• It also imperative that cooling is initiated as early as possible and definitely
prior to 6 h of postnatal life.
Which neonates should not receive TH?
• Clinical trials have generally excluded the following infants for TH –
1. those who are moribund,
2. have major congenital or genetic abnormalities,
3. neonates with severe intrauterine growth restriction,
4. those with evidence of severe coagulopathy,
5. those with evidence of severe head trauma or intracranial hemorrhage.
• There is insufficient evidence of the benefit of hypothermia
offered beyond 6h of age.
Which method is to be used for
providing TH?
• It is recommended that servo-controlled devices should be the
preferred cooling device if TH is offered as a therapeutic
option for eligible neonates.
• However, if non servo-controlled devices such as gel packs/PCM
devices are used, then it would be necessary to have 1:1 nurse.
EEG findings & seizures
• Total seizure burden is about 2.5 times higher in severe HIE vs
Moderate HIE
• Onset (moderate to severe HIE) – 13 hours of life.
• 10% - first time during rewarming.
• Maximum seizure burden – 4 hours after onset of seizures.
• acute symptomatic seizure - prolonged treatment is not
necessary.
• 4-16% - develop childhood epilepsy / infantile spasm.
• EEG background activity & evolution – prognostic value for
long-term neurodevelopmental outcome.
• Normalization of background pattern, within the 1st 24 hours
– favourable outcome
• Normal EEG pattern by 6 hours of age, that remains normal
– 100% PPV for normal outcome @ 2 years.
PPV of MRI & Spectroscopy
• Normal MRI in the first week of life – favorable outcome
• Watershed patterns – less severe outcome
• BGT & PLIC abnormalities – motor & neurocognitive
impairment @ 2-3 years of age.
• Low NAA peak & high lactate peaks – severe injury &
neurodevelopmental outcomes @ >/= 12 months of age when
measured in the basal ganglia.
Adjunctive Neuroprotective
Treatments plus TH - Erythropoietin
• Remarkable neuroprotective & reparative effects in the CNS
• Hypoxia-ischemia – Epo receptor expression is rapidly upregulated.
• If Epo is available to bind to the upregulated receptor – cell survival is
promoted.
• If Epo absent – apoptosis predominates.
• Early – anti-apoptotic & anti-inflammatory effects.
• Later – increased neurogenesis, plasticity & tissue remodeling after HI
• Phase I & 2 clinical trials – HIE treated with multiple doses of
Epo during first week of life have better neurologic outcomes
as measured by early MRI, biomarkers, 6 months & 12-24
month outcomes, even among infants with significant brain
injury on MRI.
• Phase 3 trials – final stages of execution internationally.
1. PAEAN trial, Australia – Preventing Adverse Outcomes of Neonatal
Hypoxic ischemic Encephelopathy with Erythropoietin trial
2. HEAL trial, USA – High dose Epo for Asphyxia & Encephelopathy
Xenon
• Crosses the placenta & BBB, ----- binds to N-methyl-D-aspartate glutamate
receptors to inhibit function-----thus decreasing neuronal apoptosis.
• Small multicenter trial – xenon as an adjunct to TH in UK – no serious adverse
events, no significant differences in MRI-------30% xenon for 24 hours begun
after 6 hours after birth combined with TH is not likely to improve clinical
outcome compared to TH alone.
• TOBY-Xe trial – inhibitory effect of Xenon on glutamate receptors has anti-
epileptic function & clinical effective in 5 neonates with seizures sec. to mod-
sev HIE.
• Study results of the CoolXenon 3 study - TH + 18 hours of
50% Xe inhalation in cooled infants with HIE – pending.
Argon
• More abundant than xenon, cheaper & more practcial to use
clinically as it does not require the complex rebreathing /
scavenger setup needed for xenon.
• No clinical trials
Melatonin
• Anti-apoptotic & anti-oxidative properties
• Animal studies – IV Melatonin + TH – improved cerebral energy metabolism (MRS
studies), reduced apoptosis in deep brain structures & decreased microglial
activation in the cortex at 48 hours post-injury.
• In uncooled full-term human newborns with HIE, oral administration of melatonin
(8 doses of 10mg each Q2H) started within 6 hours after birth reduced serum
malondialdehyde, a lipid peroxidation product, & nitrate/nitrite levels at 12 & 24
hours compared to untreated, uncooled controls, suggesting a role for melatonin
in reducing oxidative damage.
• Prospective trial of term newborns with HIE, melatonin
(10mg/kg daily x 5 dose) + TH vs TH alone ----- decreased
seizures on EEG & fewer white matter abnormalities on MRI
after 2 weeks of age as well as improved survival without
neurological or developmental abnormalities at 6 months of
age.
• No large RCTs have been published yet, 2 clinical trials are in
progress.
Cannabinoids
• Decreases glutamate excitotoxicity, attenuates microglia
activation, & reduces cell death.
• Animal studies – HIE improved oxygenation & EEG features.
• No clinical studies in humans are ongoing.
Allopurinol
• Xanthine oxidase inhibitor – decreases free radical & superoxide
formation
• Neuroprotective effects – when given shortly after the ischemic
insult (animal studies)
• Small RCTs – allopurinol within 4 hours of birth to neonates with
mod-sev HIE was equivocal.
• Phase 3 clinical trial ongoing.
Azithromycin
• Anti-inflammatory neuroprotective effects --- immune
modulatory properties.
• Animal studies – dose-dependant reduction in brain injury &
improvement in sensorimotor function.
• Clinical studies are in the early phase.
Stem cells
• Neuroprotection & regeneration
• Much wider therapeutic window – beneficial effects extend till
sec. & tertiary phase.
• Umbilical cord stem cell – phase 2 study – safe feasible adjunct
therapy to TH & decreased death & improved
neurodevelopmental outcome @ 1 yr.
• Timing of administration need to be studied.
Management of HIE-1.pptx

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Management of HIE-1.pptx

  • 2. Initial management, promoting adequate • Oxygenation • Ventilation • Circulation • Correction of metabolic derangements • Continous BP monitoring – low cardiac output sec. to myocardial ischemia
  • 3. • Respiratory compromise sec. to – ischemic effects on lungs, impairment of CNS, frequent exposure to MSAF & pulmonary hypertension. • Hypocarbia sec. to respiratory compensation of metabolic acidosis. – compromise cerebral autoregulation & exacerbate brain injury. • Hence, adequate management of respiratory status & blood chemistry.
  • 4. • Fluid & electrolyte imbalance – due to cerebral edema & secondary SIADH. • Hypoxia – AKI – oliguria, anuria, fluid retention & electrolyte abnormalities ( Hyponatremia) • Hyponatremia – Seizures – exacerbate brain injury & worsen cerebral edema. • Fluid & electrolyte management – critical.
  • 5. • Glucose homeostasis – often disrupted. • Hypoglycemia – exacerbate brain injury & induce seizures. • Prompt treatment of acute symptomatic seziures. • Liver injury & DIC. • DIC with bleeding – immediate treatment. • Additional vitamin K – production of vitamin K dependant clotting factors • Abnormal renal & hepatic function – metabolism & clearance of medications (phenobarbitone, Gentamicin & Furosemide)
  • 6. Hypothermia therapy • Only proven neuroprotective therapy for HIE 1. Decreases cellular metabolism by 5-8% / deg C 2. Attenuates inflammatory reaction 3. Stabilizes BBB 4. Reduces glutamate & O2 free radicals. 5. Anti-epileptic effects
  • 7. • Beneficial effect most pronounced – applied before the onset of sec. energy failure (ie, within 6 hours of birth) • Applying hypothermia within 6 hours of birth to maintain the core body temp. at 33.5+/- 0.5 degC for 72 hours followed by slow rewarming at a rate of 0.5 degC/h to normothermia, in numerous RCT to improve outcomes in neonates with mod. to severe HIE. • Alteration in pharmacokinetics – enzyme dependant metabolism (phenobarbitone, Fentanyl, Midazolam, Phenytoin, Corticosteroids & Vecuronium) - enzyme facilitated conjugation (hepatic glucuronidation – Morphine)
  • 8. • In human studies, no association of NEC with hypothermia alone or with initiation of enteral feeding. • SCFN – back & shoulders, 2.8% • Studies evaluation duration (120h vs 72 hours), depth (32 deg C vs 33.5 deg C) & initiation (6 & 24 hours) – no benefit but potential harm. • Passive cooling before active cooling if there is any delay, active cooling during transport is preferred. • Centres offering TH, should have o cEEG or aEEG o Pediatric neurologist o MRI with neuroradiology interpretation o Ancillary services – PT, ST, high risk follow up OPD
  • 9. Medication for sedation & prevention of shivering • Morphine – not evidence based, not ideal due to side effect profile – respiratory depression, urinary retention, constipation • Dexmedetomidine & Clonidine ( alpha2 adrenergic receptor agonists), specifically prevent shivering without supressing respiration. • Dexmedetomidine – reduces inflammation, neuroprotection ( animal studies)
  • 10. Outcomes of TH • Prior to TH – mortality in mod. to sev. HIE >60% & 100% in sev. HIE. • Cochrane meta analysis – 1505 term & late preterm infants with moderate to severe HIE from 11 randomized controlled trials & concluded that TH results in fewer deaths.
  • 11.
  • 13. NICHD
  • 14. TOBY
  • 15.
  • 16. HELIX
  • 17. Helix trial • Largest neonatal cooling trial reported till date • No difference between the RCT arms for the primary outcome. • Mortality at 18 months was increased in TH group.
  • 18. • Neonates who have, quick clinical recovery, a normal EEG background pattern, a normal MRI, & a normal neurological examination at 7 to 10 days of age often have a favorable long-term outcome.
  • 19. National Neonatology Forum, India Position Statement and Guidelines For Use of Therapeutic Hypothermia to treat Neonatal Hypoxic Ischemic Encephalopathy In India October 2021
  • 20. • 1. TH likely to decrease death or severe disability and cerebral palsy at 18-24 months even in LMICs as compared to HICs. • 2. There is significant heterogeneity in the studies from LMICs compared to HICs which reported mortality prior to discharge following TH in neonates with HIE. The pooled estimates for mortality prior to discharge showed a significant benefit in favour of TH (RR 0.77, 95%CI 0.62-0.94) in HICs. In the studies from LMICs there was uncertainty (RR: 0.74; 0.53 to 1.02); a possible reason could be the lack of certainty of the encephalopathy being due to an asphyxial insult.
  • 21. 3. Mortality before discharge when analyzed for infants with moderate- severe HIE with cord pH <7.0 showed no significant heterogeneity in studies from HICs and LMICs and significant benefit in favour of TH in both subsets (HICRR 0.69,0.54-0.88; LMIC- RR 0.58, 0.43-0.79). However, in studies that reported cord pH>7.0 or did not report cord pH, there was considerable heterogeneity and no benefit in survival prior to discharge. 4. In neonates with hypothermia at admission and unclear evidence of severe intrapartum asphyxia (cord pH>7.0 or cord pH not available - more often seen amongst outborn neonates in LMICs) there is uncertainty of the benefit from TH (ranging from benefit to harm).
  • 22. 5. As the risk of death increases with severe encephalopathy, need for invasive ventilation, and inotropic support, availability of optimum neonatal intensive care facilities is essential if TH is to be offered at a health facility.
  • 23. Which neonates should be offered TH? • It is recommended that TH should be offered to neonates with HIE with gestational age > 36 weeks, <6 hrs of age of life and with admission temperature 36-37.4 degC, IF they fulfil all of the following criteria: 1. pH<7 or BE >-16 on cord or arterial blood gas done within 1 h of life AND • Apgar score < 5 at 10 minutes or at least 10 min of positive pressure ventilation AND • history of acute perinatal event (such as but not limited to placental abruption, uterine rupture, cord prolapse) 2. Evidence of moderate or severe encephalopathy
  • 24. • During preparation for cooling if the neonate’s encephalopathy has improved (becomes mild or normal), therapeutic hypothermia may be deferred and neonate observed closely and offered continued supportive care • Prior to initiating TH it must be ensured that parents are provided sufficient information about the benefits and harms of cooling, the details of the procedure and outcomes. • A written consent must be obtained from parents/legal guardians. • It must be ensured that the neonate’s cardio-respiratory status is stable prior to initiating cooling. • It also imperative that cooling is initiated as early as possible and definitely prior to 6 h of postnatal life.
  • 25. Which neonates should not receive TH? • Clinical trials have generally excluded the following infants for TH – 1. those who are moribund, 2. have major congenital or genetic abnormalities, 3. neonates with severe intrauterine growth restriction, 4. those with evidence of severe coagulopathy, 5. those with evidence of severe head trauma or intracranial hemorrhage. • There is insufficient evidence of the benefit of hypothermia offered beyond 6h of age.
  • 26. Which method is to be used for providing TH? • It is recommended that servo-controlled devices should be the preferred cooling device if TH is offered as a therapeutic option for eligible neonates. • However, if non servo-controlled devices such as gel packs/PCM devices are used, then it would be necessary to have 1:1 nurse.
  • 27.
  • 28.
  • 29. EEG findings & seizures • Total seizure burden is about 2.5 times higher in severe HIE vs Moderate HIE • Onset (moderate to severe HIE) – 13 hours of life. • 10% - first time during rewarming. • Maximum seizure burden – 4 hours after onset of seizures. • acute symptomatic seizure - prolonged treatment is not necessary. • 4-16% - develop childhood epilepsy / infantile spasm.
  • 30. • EEG background activity & evolution – prognostic value for long-term neurodevelopmental outcome. • Normalization of background pattern, within the 1st 24 hours – favourable outcome • Normal EEG pattern by 6 hours of age, that remains normal – 100% PPV for normal outcome @ 2 years.
  • 31. PPV of MRI & Spectroscopy • Normal MRI in the first week of life – favorable outcome • Watershed patterns – less severe outcome • BGT & PLIC abnormalities – motor & neurocognitive impairment @ 2-3 years of age. • Low NAA peak & high lactate peaks – severe injury & neurodevelopmental outcomes @ >/= 12 months of age when measured in the basal ganglia.
  • 32. Adjunctive Neuroprotective Treatments plus TH - Erythropoietin • Remarkable neuroprotective & reparative effects in the CNS • Hypoxia-ischemia – Epo receptor expression is rapidly upregulated. • If Epo is available to bind to the upregulated receptor – cell survival is promoted. • If Epo absent – apoptosis predominates. • Early – anti-apoptotic & anti-inflammatory effects. • Later – increased neurogenesis, plasticity & tissue remodeling after HI
  • 33. • Phase I & 2 clinical trials – HIE treated with multiple doses of Epo during first week of life have better neurologic outcomes as measured by early MRI, biomarkers, 6 months & 12-24 month outcomes, even among infants with significant brain injury on MRI. • Phase 3 trials – final stages of execution internationally. 1. PAEAN trial, Australia – Preventing Adverse Outcomes of Neonatal Hypoxic ischemic Encephelopathy with Erythropoietin trial 2. HEAL trial, USA – High dose Epo for Asphyxia & Encephelopathy
  • 34. Xenon • Crosses the placenta & BBB, ----- binds to N-methyl-D-aspartate glutamate receptors to inhibit function-----thus decreasing neuronal apoptosis. • Small multicenter trial – xenon as an adjunct to TH in UK – no serious adverse events, no significant differences in MRI-------30% xenon for 24 hours begun after 6 hours after birth combined with TH is not likely to improve clinical outcome compared to TH alone. • TOBY-Xe trial – inhibitory effect of Xenon on glutamate receptors has anti- epileptic function & clinical effective in 5 neonates with seizures sec. to mod- sev HIE.
  • 35. • Study results of the CoolXenon 3 study - TH + 18 hours of 50% Xe inhalation in cooled infants with HIE – pending.
  • 36. Argon • More abundant than xenon, cheaper & more practcial to use clinically as it does not require the complex rebreathing / scavenger setup needed for xenon. • No clinical trials
  • 37. Melatonin • Anti-apoptotic & anti-oxidative properties • Animal studies – IV Melatonin + TH – improved cerebral energy metabolism (MRS studies), reduced apoptosis in deep brain structures & decreased microglial activation in the cortex at 48 hours post-injury. • In uncooled full-term human newborns with HIE, oral administration of melatonin (8 doses of 10mg each Q2H) started within 6 hours after birth reduced serum malondialdehyde, a lipid peroxidation product, & nitrate/nitrite levels at 12 & 24 hours compared to untreated, uncooled controls, suggesting a role for melatonin in reducing oxidative damage.
  • 38. • Prospective trial of term newborns with HIE, melatonin (10mg/kg daily x 5 dose) + TH vs TH alone ----- decreased seizures on EEG & fewer white matter abnormalities on MRI after 2 weeks of age as well as improved survival without neurological or developmental abnormalities at 6 months of age. • No large RCTs have been published yet, 2 clinical trials are in progress.
  • 39. Cannabinoids • Decreases glutamate excitotoxicity, attenuates microglia activation, & reduces cell death. • Animal studies – HIE improved oxygenation & EEG features. • No clinical studies in humans are ongoing.
  • 40. Allopurinol • Xanthine oxidase inhibitor – decreases free radical & superoxide formation • Neuroprotective effects – when given shortly after the ischemic insult (animal studies) • Small RCTs – allopurinol within 4 hours of birth to neonates with mod-sev HIE was equivocal. • Phase 3 clinical trial ongoing.
  • 41. Azithromycin • Anti-inflammatory neuroprotective effects --- immune modulatory properties. • Animal studies – dose-dependant reduction in brain injury & improvement in sensorimotor function. • Clinical studies are in the early phase.
  • 42. Stem cells • Neuroprotection & regeneration • Much wider therapeutic window – beneficial effects extend till sec. & tertiary phase. • Umbilical cord stem cell – phase 2 study – safe feasible adjunct therapy to TH & decreased death & improved neurodevelopmental outcome @ 1 yr. • Timing of administration need to be studied.