PERINATAL ASPHYXIA PATHOPHYSIOLOGYICAL PARADOX AND RECENT TRENDS IN MANAGEMENT

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PERINATAL ASPHYXIA PATHOPHYSIOLOGYICAL PARADOX
AND RECENT TRENDS IN MANAGEMENT

• Dr. A. K. Dutta
• Director Prof. HOD, Pediatrics
• Kalawati Saran Childrens Hospital
• Lady Harding Medical College
• New Delhi

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PERINATAL ASPHYXIA

• Insult to the fetus / Newborn
• Lack of oxygen (Hypoxia)
• Lack of perfusion (Ischemia)
• Effect of hypoxia Ischemia inseperable
• Both contribute to tissue injury

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ESSENTIAL CRITERIA FOR PERINATAL ASPHYXIA

• Prolonged metabolic or mixed acidemia (pH lt 7.00)
  on an umbilical cord arterial blood sample
• Persistence of an Apgar score of 0-3 for gt 5
  minutes
• Clinical neurological manifestations e.g.
  seizure, hypotonia, coma or hypoxic-ischaemic
  encephalopathy in the immediate neonatal period
• Evidence of multiorgan system dysfunction in the
  immediate neonatal periods

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PERINATAL ASPHYXIA
Western Scenario
India (NNF data Base)
Incidence Cause of Perinatal death Still Birth
P. Mort.
1 1.5 / 1000 20 50
10 26 59
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ETIOLOGY

• Intrapartum or Antepartum (90)
• Placental Insufficiency
• Post partum (10)
• Pulmonary
• Cardiovascular
• Neurologic Insufficiency

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FACTORS

• ? Mat. Oxygenation

? Blood flow mother to placenta
? Fetal O2 Req.
? Gas Exchange across placenta or fetal tissue
? Blood flow placenta to fetus
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PATHOPHYSIOLOGY

• Hypoxia

Diving seal reflex
Shunting of blood to brain adrenals heart
Away from lungs, kidney gut skin
NON BRAIN ORGAN INJURY
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PATHOPHYSIOLOGY

• Asphyxia continues

Shunting within the brain
Anterior Circulation Suffers
Posterior Circulation Maintained
CEREBRAL CORTICAL LESIONS
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PATHOPHYSIOLOGY

• Near total asphyxia
• Cord accidents
• Maternal CP arrest
• Hypoxia ABRUPT SEVERE
• No time for compensation

THALAMUS BRAIN STEM INJURY, CORTEX SPARED
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PATHOLOGY

• Target organs of perinatal asphyxia
• Kidneys 50
• Brain 28
• Heart 25
• Lung 23
• Liver, Bowel, Bone marrow lt 5

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NEUROPATHOLOGICAL CHANGES

• Pattern seen in term babies
• Selective neuronal necrosis (Spastic CP)
• Status Marmoratus (Chorea, Athetoid, Dystonia)
• Parasagittal cerebral injury (Prox Spastic
  Quadriparesis)
• Focal and multifocal ischemic brain injury (sp.
  Hemiparesis, cognitive defects, seizure)
• Pattern predominant in preterm
• Periventricular leukomalacia

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PATHOLOGY

• Cerebral O2 ?
• Substrate supply ?
• Synaptic inactivation (Reversible)
• Energy failure
• Memb. pump failure

At cellular level
Further ? in perfusion
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ISCHEMIA-RELATED GENERATION OF HYPOXANTHINE

• I
• S
• C
• H
• E
• M
• I
• A

ATP ?? AMP? ? Adenosine ? ? Inosine ?
? Hypoxanthine
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ISCHEMIA AND REPERFUSION INJURY

• Ischemia

ATP depletion
Calcium influx
Phospholipase activation
Arachidonic acid release
Prostaglandins
Proteases, lipases
Vasodilation
Microvascular permeability
Reperfusion
ROS Release
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MECHANISM

• RESUSCITATION

ATP
ASPHYXIA
HYPOXANTHINE
Oxygen
Oxygen free radicals
BLOCKED
XANTHINE
Oxygen
BLOCKED
Oxygen free radicals
URIC ACID
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FREE RADICAL

• Unpaired
• Highly reactive

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EFFECT OF ROS

• ROS

DNA strand breakage
Lipid peroxidation
Neutrophil accumulation
Release of proteases, myeloperoxidase,
prostaglandins
PMN plugging of capillaries
Membrane damage
Phagocytosis
Ischemia
Cell death
Tissue damage
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HIE

• ? Glutamate release

NMDA receptor
Neurotoxic
Ca Accumulation In neurones
Neurtoxicity in HIE
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CLINICAL MANIFESTATIONS OF HIE

• Altered consciousness
• Tone problems
• Seizure activity
• Autonomic disturbances
• Abnormalities of peripheral and stem reflexes

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CLASSIFICATION OF HIE (LEVENE)
Mild
Moderate
Feature
Severe
Consciousness Tone Seizure Sucking / Resp.
Irritable Hypotonia No Poor Suck
Lethargy Marked Yes Unable to suck
Comatose Severe Prolonged Unable to sustain
spont. Resp.
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SPECIFIC MANAGEMENTPREVENT FURTHER BRAIN DAMAGE

• Maintain temperature, perfusion, oxygenation
  ventilation
• Correct maintain normal metabolic acid base
  milieu
• Prompt management of complications

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SUMMARY OF INITIAL MANAGEMENT

• Admit in newborn unit
• Maintenance of temp
• Check vital signs
• Check hematocrit, sugar, ABG, electrolyte
• I.V line
• Consider vol. expander
• Vit K, stomach wash, urine vol

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SUPPORTIVE CARE

• TABCFMFMCF
• T - Temperature
• A - Airway
• B - Breathing
• C - Circulation
• F - Fluid
• M - Medications
• F - Feed
• M - Monitoring
• C - Communication
• F - Followup

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SUBSEQUENT MANAGEMENT

• Oxygenation ventilation
• Adequate perfusion
• Normal glucose calcium
• Normal hematocrit
• Treat seizure

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TREATMENT OF SEIZURES

• Correction of hypoglycemia, hypocalcemia
  electrolyte
• Prophylactic Phenobarbitone ?
• Therapeutic Phenobarbitone 20 mg / kg (loading),
  5 mg / kg / d (maintenance)
• Lorazepam 0.05 0.1 mg / kg
• Diazepam to be avoided

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CEREBRAL OEDEMA

• Avoid fluid overload (SIADH, ATN)
• 30? Head raise
• Maintain PaCo2 25-30mm Hg in ventilated infants
• Mannitol 20 (0.5 - 1g / kg) 6 hrly. x 24 hrs.
• Frusemide 1.0 mg / kg every 12 hrs.

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PERFUSIONCFT deranged

• Maintain MAP to maintain CBF
• Maintain CVP 5-8mm Hg Term 3-5mm Hg Preterm
• Avoid Fluid, Colloid SBC Boluses
• Replace volume slowly

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SUPPORTIVE CARE (RECENT ADVANCES)

• Role of Mannitol, Steriod Hyperglycemia ??
• Regulatory gene (Regulon)
• Hypothermia
• Pentoxifylline
• Enhancement of natural defence
• - Neurotrophic factor fibroblast growth factor

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POTENTIAL THERAPEUTIC STRATEGIES
Target
Compounds
Approach
Blockade of free-radical generation Scavenging of
oxidants after generation Blocking chain
propagation of secondary oxidants Substrate
manipulation
Xanthine oxidase inhibitors Antioxidant
enzymes Radical scavengers IronCalciumGluco
se
Allopurinol Oxypurinol SOD, Catalase,
Glutathione, N-AcetylcysteineDMSO, DMTU,
21- Aminosteroids ?-Tocopherol Deferoxamine
calcium blockers ?Increase glucose stores
(Contd)
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POTENTIAL THERAPEUTIC STRATEGIES
Target
Compounds
Approach
Blockade of secondary metabolites or
inflammatory mediators Blockade of
coagulation effects Inhibition of excitatory
amino acids Enhancing endogenous antioxidant
capability
PAFPhospholipases NeutrophilsBlock
platelet adhesionGlutamate receptor (NMDA)
antagonists Regulon regulation
PAF antagonists Phospholipase inhibitors
(quinacrine, hydrocortisone) Selection blockers
Reduce activation Block adhesion PAF receptor
blockers Magnesium MK 801
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PREDICTORS OF POOR NEURO DEVELOPMENTAL OUTCOME

• Failure to establish respiration by 5 minutes
• Apgar 3 or less in 5 mts
• Onset of Seizure in 12 hrs
• Refractory convulsion
• Stage III HIE
• Inability to establish oral feed by 1 wk
• Abnormal EEG failure to normalise by 7 days of
  life
• Abnormal CT, MRI, MR spectroscopy in neonatal
  period

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HIE OUTCOME (METAANALYSIS)
Severe
Moderate
Mild
Risk of Death Risk of Severe disability
61 72
5.6 20
lt 1 lt 1
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FUTURE DIRECTIONS

• No single magic bullet agent
• Multitier combination therapies

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THE FINAL R
RELAX
Thank you