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RECENT ADVANCES IN TREATMENT OF HIE
BY
DR.TAUHID IQBALI
MBBS(JIPMER)
MD PED. (PMCH)
DEFNITION OF HIE
NEONATAL ENCEPHALOPATHY FOLLOWING
SEVERE BIRTH ASPHYXIA OR PERINATAL
HYPOXIA IS REFEREDTO AS HIE
PATHOPHYSIOLOGY OF HIE
 Pathogenesis of HIE involves cascades of events.
And it consist of:
1. Primary energy failure
2. Latent phase
3. Reperfusion injury
4 .Secondary phase
PRIMARY ENERGY FAILURE
SEVERE HYPOXIA
DEPLETON OF HIGH ENERGY PHOSPHATE COMPOUNDSINCREASE RELEASE OF GLUTAMATE AT SYNAPTIC LEVEL
FAILURE OF Na+-k+ ATPase
DEPOLARIZATION OF CELL MEMBRANE
INFLUX OF Na+ INFLUX OF Ca++
OSMOTIC INFLUX OF WATER
CYTOTOXIC NEURONAL EDEMA
ACTIVATION OF
INTRACELLULAR
PROTEASES AND
LIPASES
PRODUCTION OF:
XANTHINE OXIDASE
NO
PROSTAGLANDINS
FREE RADICAL GENERATION
NMDA RECEPTOR ACTIVATION
Ca ++ INFLUX
NEURONAL NOS ACTIVATION
INCREASE NO RELEASE
NO AND FREE RADICALS COMBINETO FORM
PEROXYNITRITE ( A HIGHLYTOXIC OXIDAND )
NECROTIC CELL DEATHOF NEURONS
LATENT PHASE
PHASEWHERE CEREBRAL METABOLISM
TRANSIANTLY RECOVERS
REPERFUSION PHASE
1.ACTIVATION OF : Cyclooxygenase
Xanthine oxidase
Lipoxygenase
INCREASE PRODUCTION OF FREE RADICAL
2. ACCUMULATION OF NO
SECONDARY PHASE
IT INVOLVESCONTRIBUTIONSOF:
MITOCHONDRIAL DYSFUNCTION
CASPASEACTIVATION
INFLAMATORY MEDIATORS
EXCITOTOXIC – OXIDATIONCASCADES
APOPTOTICCELL DEATH
PATHOPHYSIOLOGY OF HIE CONT.
TIME LINE
SO NOW ASWE UNDERSTOODTHE
CURRENT MECHANISM OF HIE !!
OUR STRATEGIES WOULD BE TO:
 DECREASE CEREBRAL METABOLIC RATE
 BLOCK NMDA RECEPTOR CHANNEL
 DECREASE GLUTAMATE RELEASE
 INHIBIT VOLTAGE GATED Ca++ CHANNELS
 DECREASE FREE RADICAL REACTIONS
 PREVENT FREE RADICAL FORMATIONS
 DECREASE INFLAMATORY RESPONSE
 ATTENUATE APOPTOSIS CASCADES
THIS ISWHAT GIVES US HUNTING GROUND
FOR ADVANCEDTHERAPUTIC MODALITIES IN
HIE
RECENT ADVANCES IN MANAGEMENT OF HIE
HYPOTHERMIA THERAPY
MILD HYPOTHERMIA (3-4 degree below baseline temperature) IS NEUROPROTECTIVE
MECHANISM OF ACTION:
1.DECREASE CEREBRAL METABOLICRATE AND ENERGY DEPLETION
2.DECREASE EXCITATORY NEUROTRANSMITTER RELEASE
3.DECREASE APOPTOSIS
4.DECREASE VASCULAR PERMEABILITY AND EDEMA
What is the optimal timing of initiation of
hypothermia therapy?
Cooling must begin early, within 6 hours of
injury. However, experimental evidence
strongly suggest that the earlier the better.
What is the optimal duration of hypothermia
therapy?
The greater the severity of the initial injury,
the longer the duration of hypothermia
needed.
But it should be at least used for 72 hours
What is the best method?
Two methods have been used in clinical trials:
Selective head cooling
Whole body cooling
In selective head cooling, a cap (Cool Cap) with channels for circulating cold water is
placed over the infant's head, and a pumping device facilitates continuous circulation
of cold water. Nasopharyngeal or rectal temperature is then maintained at 34-35°C
for 72 hours
In whole body hypothermia, the infant is placed on a commercially available cooling
blanket, through which circulating cold water flows, so that the desired level of
hypothermia is reached quickly and maintained for 72 hours.
What is the optimal rewarming method?
Rewarming is a critical period. In clinical trials,
rewarming was carried out gradually, over 6-8
hours.
ADVERSE EFFECTS:
THOUGHTHEORETITAL IT INCLUDES
COAGULATION DEFECT
LEUKOCYTES MALFUNCTION
PULMONARY HYPERTENSION
WORSENINGOF METABOLICACIDOSIS
ABNORMALITIESOF CARDIAC RHYTHM
2013 Cochrane review says
Significant adverse effect is limited to only SINUS BRADYCARDIA and
THROMBOCYTOPENIA
LONGTERM OUTCOME:
2012 NICHD trial
Combined outcome of death and IQ score below
70 occurred in
62% of patient in control group
47% of patient in hypothermia therapy group
Death
Control group 48%
Hypothermia therapy group 28%
Severe disability
Control group 60%
Hypothermia therapy group 41%
STUDIES ONTHERAPUTIC HYPOTHERMIA IN HIE
A decrease in the combined outcomes of mortality/major
neurodevelopmental disability at 18 months (8 studies)
A reduction in mortality (11 studies)
A reduction in neurodevelopmental disability in survivors (8 studies)
9 independent meta-analyses have confirmed a consistent and
robust beneficial effect of therapeutic hypothermia for moderate-
to-severe encephalopathy
OTHER NEWTHERAPUTIC MODALITIES
OXYGEN FREE RADICAL INHIBITOR AND SCAVENGERS
DIRECT INHIBITORS:
SUPEROXIDE DISMUTASE
ENDOPEROXIDASE
CATALASE
SCAVENGERS:
VITAMIN E
VITAMIN C
MANNITOL
INDIRECT INHIBITORS:
INDOMETHACIN
ALLOPURINOL
CYCLOOXYGENASE
N-ACETYLCYSTEINE
MELATONIN
Study have shown promising results but
their use will depend on the ability to
develop appropriate delivery system
that will allow action at the cellular and
specific tissue site
CALCIUM CHANNEL BLOCKERS
FLUNARIZINE
NIMODIPINE
These two drugs appears mot efficacious on animal study
Results of clinical trial is awaited
ERYTHROPOIETIN
Its neuroprotective mechanism is mediated through:
1.Direct neurotropic effect
2.Decrease susceptibility to glutamate toxicity
3. Release of antiapoptotic factors
4.Reduce inflamation
5. Decrease nitric oxide mediated injury
6.Direct antioxidant effect
Epo 5000 u/kg have shown to provide significant neuroprotection
and improved outcome
EXCITATORYAMINO ACID ANTAGONIST
INHIBITOR OF GLUTAMATE RELEASE:
BACLOFEN
ADENOSINE
ADENOSINEAGONIST
NMDA RECEPTOR BLOCKER:
MAGNESIUM
PHENCYCLIDINE
DEXTROMETHORPHAN
KETAMINE
MK- 801
EAA antagonist MK-801 , has shown promising results in experimental animals and in a limited
number of adult trials. However, this drug has serious cardiovascular adverse effects
HOWEVER
MAGNESIUM SULFATE ISA NATURALANTAGONISTOF NMDA WITH LESS SIDE EFFECTS SO ROLE OF MS ASA
NEUROPROTECTIVEAGENT IN PREVENTION OF BRAIN DAMAGE IN HIE DESERVE ACTIVECONSIDERATION
AND EVALUATION IN FUTURE
PREVENTION OF EXCESS NITRIC OXIDE FORMATION
NOS INHIBITOR:
NITROARGININE
Administration of nitroarginine in immature rats caused prolonged
inhibition of NOS and thus reduction in the extent of brain injury
Agents decreasing inflamatory response:
Allopurinol
Inflamatory antagonist
IL1 blocker
TNF alfa blocker
ATTENUATEAPOPTOSIS PATHWAY
CASPASE INHIBITORS
STEM CELLTRANSPLANTATION
THERE IS EVIDENCETHAT SUGGEST NEONATE BRAIN IS ENDOWED
WITHTHE CAPABILITY FOR ENDOGENOUS NEUROGENESIS FLOWING
HIE
INFACT MANY EXPERIMENTAL EVIDENCES SUGGEST SCT MAY REPAIR
THE DAMAGED NEURONSIN BRAIN
SEVERAL TYPES OF STEM CELLS HAVE BEEN USED IN RODENTS
INCLUDING NEURONAL STEM CELLS MESNCHYMAL STEM CELLS AND
HEMATOPOIETIC STEM CELLS
THERE IS EVIDENCETHAT SUGGESTTHAT GENETICALLY MODIFIED
STEM CELLS MAY BE MORE EFFECTIVETHAN UNMODIFIED STEM CELLS
THUS SCT HAS POTENTIALTO BECOMEA FUTURE NEUROPROTECTIVE
AND REGENERATIVETHERAPY FOR HIE
THANK YOU

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RECENT ADVANCES IN MANAGEMENT OF HIE

  • 1. RECENT ADVANCES IN TREATMENT OF HIE BY DR.TAUHID IQBALI MBBS(JIPMER) MD PED. (PMCH)
  • 2. DEFNITION OF HIE NEONATAL ENCEPHALOPATHY FOLLOWING SEVERE BIRTH ASPHYXIA OR PERINATAL HYPOXIA IS REFEREDTO AS HIE
  • 3. PATHOPHYSIOLOGY OF HIE  Pathogenesis of HIE involves cascades of events. And it consist of: 1. Primary energy failure 2. Latent phase 3. Reperfusion injury 4 .Secondary phase
  • 4. PRIMARY ENERGY FAILURE SEVERE HYPOXIA DEPLETON OF HIGH ENERGY PHOSPHATE COMPOUNDSINCREASE RELEASE OF GLUTAMATE AT SYNAPTIC LEVEL FAILURE OF Na+-k+ ATPase DEPOLARIZATION OF CELL MEMBRANE INFLUX OF Na+ INFLUX OF Ca++ OSMOTIC INFLUX OF WATER CYTOTOXIC NEURONAL EDEMA ACTIVATION OF INTRACELLULAR PROTEASES AND LIPASES PRODUCTION OF: XANTHINE OXIDASE NO PROSTAGLANDINS FREE RADICAL GENERATION NMDA RECEPTOR ACTIVATION Ca ++ INFLUX NEURONAL NOS ACTIVATION INCREASE NO RELEASE NO AND FREE RADICALS COMBINETO FORM PEROXYNITRITE ( A HIGHLYTOXIC OXIDAND ) NECROTIC CELL DEATHOF NEURONS
  • 5. LATENT PHASE PHASEWHERE CEREBRAL METABOLISM TRANSIANTLY RECOVERS
  • 6. REPERFUSION PHASE 1.ACTIVATION OF : Cyclooxygenase Xanthine oxidase Lipoxygenase INCREASE PRODUCTION OF FREE RADICAL 2. ACCUMULATION OF NO
  • 7. SECONDARY PHASE IT INVOLVESCONTRIBUTIONSOF: MITOCHONDRIAL DYSFUNCTION CASPASEACTIVATION INFLAMATORY MEDIATORS EXCITOTOXIC – OXIDATIONCASCADES APOPTOTICCELL DEATH
  • 8. PATHOPHYSIOLOGY OF HIE CONT. TIME LINE
  • 9. SO NOW ASWE UNDERSTOODTHE CURRENT MECHANISM OF HIE !!
  • 10. OUR STRATEGIES WOULD BE TO:  DECREASE CEREBRAL METABOLIC RATE  BLOCK NMDA RECEPTOR CHANNEL  DECREASE GLUTAMATE RELEASE  INHIBIT VOLTAGE GATED Ca++ CHANNELS  DECREASE FREE RADICAL REACTIONS  PREVENT FREE RADICAL FORMATIONS  DECREASE INFLAMATORY RESPONSE  ATTENUATE APOPTOSIS CASCADES
  • 11. THIS ISWHAT GIVES US HUNTING GROUND FOR ADVANCEDTHERAPUTIC MODALITIES IN HIE
  • 13. HYPOTHERMIA THERAPY MILD HYPOTHERMIA (3-4 degree below baseline temperature) IS NEUROPROTECTIVE MECHANISM OF ACTION: 1.DECREASE CEREBRAL METABOLICRATE AND ENERGY DEPLETION 2.DECREASE EXCITATORY NEUROTRANSMITTER RELEASE 3.DECREASE APOPTOSIS 4.DECREASE VASCULAR PERMEABILITY AND EDEMA
  • 14. What is the optimal timing of initiation of hypothermia therapy? Cooling must begin early, within 6 hours of injury. However, experimental evidence strongly suggest that the earlier the better.
  • 15. What is the optimal duration of hypothermia therapy? The greater the severity of the initial injury, the longer the duration of hypothermia needed. But it should be at least used for 72 hours
  • 16. What is the best method? Two methods have been used in clinical trials: Selective head cooling Whole body cooling In selective head cooling, a cap (Cool Cap) with channels for circulating cold water is placed over the infant's head, and a pumping device facilitates continuous circulation of cold water. Nasopharyngeal or rectal temperature is then maintained at 34-35°C for 72 hours In whole body hypothermia, the infant is placed on a commercially available cooling blanket, through which circulating cold water flows, so that the desired level of hypothermia is reached quickly and maintained for 72 hours.
  • 17. What is the optimal rewarming method? Rewarming is a critical period. In clinical trials, rewarming was carried out gradually, over 6-8 hours.
  • 18. ADVERSE EFFECTS: THOUGHTHEORETITAL IT INCLUDES COAGULATION DEFECT LEUKOCYTES MALFUNCTION PULMONARY HYPERTENSION WORSENINGOF METABOLICACIDOSIS ABNORMALITIESOF CARDIAC RHYTHM 2013 Cochrane review says Significant adverse effect is limited to only SINUS BRADYCARDIA and THROMBOCYTOPENIA
  • 19. LONGTERM OUTCOME: 2012 NICHD trial Combined outcome of death and IQ score below 70 occurred in 62% of patient in control group 47% of patient in hypothermia therapy group Death Control group 48% Hypothermia therapy group 28% Severe disability Control group 60% Hypothermia therapy group 41%
  • 20. STUDIES ONTHERAPUTIC HYPOTHERMIA IN HIE A decrease in the combined outcomes of mortality/major neurodevelopmental disability at 18 months (8 studies) A reduction in mortality (11 studies) A reduction in neurodevelopmental disability in survivors (8 studies) 9 independent meta-analyses have confirmed a consistent and robust beneficial effect of therapeutic hypothermia for moderate- to-severe encephalopathy
  • 21. OTHER NEWTHERAPUTIC MODALITIES OXYGEN FREE RADICAL INHIBITOR AND SCAVENGERS DIRECT INHIBITORS: SUPEROXIDE DISMUTASE ENDOPEROXIDASE CATALASE SCAVENGERS: VITAMIN E VITAMIN C MANNITOL INDIRECT INHIBITORS: INDOMETHACIN ALLOPURINOL CYCLOOXYGENASE N-ACETYLCYSTEINE MELATONIN Study have shown promising results but their use will depend on the ability to develop appropriate delivery system that will allow action at the cellular and specific tissue site
  • 22. CALCIUM CHANNEL BLOCKERS FLUNARIZINE NIMODIPINE These two drugs appears mot efficacious on animal study Results of clinical trial is awaited ERYTHROPOIETIN Its neuroprotective mechanism is mediated through: 1.Direct neurotropic effect 2.Decrease susceptibility to glutamate toxicity 3. Release of antiapoptotic factors 4.Reduce inflamation 5. Decrease nitric oxide mediated injury 6.Direct antioxidant effect Epo 5000 u/kg have shown to provide significant neuroprotection and improved outcome
  • 23. EXCITATORYAMINO ACID ANTAGONIST INHIBITOR OF GLUTAMATE RELEASE: BACLOFEN ADENOSINE ADENOSINEAGONIST NMDA RECEPTOR BLOCKER: MAGNESIUM PHENCYCLIDINE DEXTROMETHORPHAN KETAMINE MK- 801 EAA antagonist MK-801 , has shown promising results in experimental animals and in a limited number of adult trials. However, this drug has serious cardiovascular adverse effects HOWEVER MAGNESIUM SULFATE ISA NATURALANTAGONISTOF NMDA WITH LESS SIDE EFFECTS SO ROLE OF MS ASA NEUROPROTECTIVEAGENT IN PREVENTION OF BRAIN DAMAGE IN HIE DESERVE ACTIVECONSIDERATION AND EVALUATION IN FUTURE
  • 24. PREVENTION OF EXCESS NITRIC OXIDE FORMATION NOS INHIBITOR: NITROARGININE Administration of nitroarginine in immature rats caused prolonged inhibition of NOS and thus reduction in the extent of brain injury Agents decreasing inflamatory response: Allopurinol Inflamatory antagonist IL1 blocker TNF alfa blocker
  • 25. ATTENUATEAPOPTOSIS PATHWAY CASPASE INHIBITORS STEM CELLTRANSPLANTATION THERE IS EVIDENCETHAT SUGGEST NEONATE BRAIN IS ENDOWED WITHTHE CAPABILITY FOR ENDOGENOUS NEUROGENESIS FLOWING HIE INFACT MANY EXPERIMENTAL EVIDENCES SUGGEST SCT MAY REPAIR THE DAMAGED NEURONSIN BRAIN SEVERAL TYPES OF STEM CELLS HAVE BEEN USED IN RODENTS INCLUDING NEURONAL STEM CELLS MESNCHYMAL STEM CELLS AND HEMATOPOIETIC STEM CELLS THERE IS EVIDENCETHAT SUGGESTTHAT GENETICALLY MODIFIED STEM CELLS MAY BE MORE EFFECTIVETHAN UNMODIFIED STEM CELLS THUS SCT HAS POTENTIALTO BECOMEA FUTURE NEUROPROTECTIVE AND REGENERATIVETHERAPY FOR HIE