perinatal asphyxia
TRANSCRIPT
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PERINATAL ASPHYXIA – PATHOPHYSIOLOGYICAL PARADOX AND
RECENT TRENDS IN MANAGEMENT
Dr Varsha Atul shah
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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 < 7.00) on an umbilical cord arterial blood sample
Persistence of an Apgar score of 0-3 for > 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
Blood flow placenta to fetus
Gas Exchange across placenta or fetal tissue
Fetal O2 Req.
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PATHOPHYSIOLOGYHypoxia
Diving seal reflex
Shunting of blood to brain adrenals & heart
Away from lungs, kidney gut & skin
NON BRAIN ORGAN INJURYNON BRAIN ORGAN INJURY
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PATHOPHYSIOLOGYAsphyxia continues
Shunting within the brain
Anterior Circulation
Suffers
Posterior Circulation Maintained
CEREBRAL CORTICAL LESIONSCEREBRAL 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 SPAREDTHALAMUS & 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 < 5%
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NEUROPATHOLOGICAL CHANGES 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
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
Further in perfusion
At cellular level
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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 INJURYIschemia ATP
depletionCalcium influx
Phospholipase activation
Arachidonic acid release
Prostaglandins Proteases, lipases
Vasodilation
Microvascular permeabilityReperfusion
ROS ReleaseROS Release
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MECHANISM
RESUSCITATION ATP ASPHYXIA
HYPOXANTHINE
XANTHINE
URIC ACID
Oxygen
Oxygen free radicals
Oxygen
Oxygen free radicals
BLOCKED
BLOCKED
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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
Tissue damage
Phagocytosis
PMN plugging of capillaries
Ischemia
Membrane damage
Cell death
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HIE
Glutamate release
Glutamate release
NMDA receptorNMDA receptor
Ca Accumulation In neurones
Ca Accumulation In neurones
Neurtoxicity in HIENeurtoxicity in HIE
NeurotoxicNeurotoxic
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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
Consciousness
Tone
Seizure
Sucking / Resp.
Irritable
Hypotonia
No
Poor Suck
Lethargy
Marked
Yes
Unable to suck
Feature Severe
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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TABCFMFMCF T - Temperature A - Airway B - Breathing C - Circulation F - Fluid M - Medications F - Feed M - Monitoring C -
Communication F - Followup
SUPPORTIVE CARE
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SUBSEQUENT MANAGEMENTSUBSEQUENT MANAGEMENT
Oxygenation & ventilation
Adequate perfusion
Normal glucose & calcium
Normal hematocrit
Treat seizure
Oxygenation & ventilation
Adequate perfusion
Normal glucose & calcium
Normal hematocrit
Treat seizure
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TREATMENT OF SEIZURESTREATMENT 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
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 – Term3-5mm Hg –
Preterm
Avoid Fluid, Colloid & SBC Boluses
Replace volume slowly
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SUPPORTIVE CARE (RECENT ADVANCES)SUPPORTIVE CARE (RECENT ADVANCES)
Role of Mannitol, Steriod & Hyperglycemia ??
Regulatory gene (Regulon)
Hypothermia
Pentoxifylline
Enhancement of natural defence
- Neurotrophic factor & fibroblast growth factor
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 STRATEGIESTarget Compounds
Blockade of free-radical generation
Scavenging of oxidants after generation
Blocking chain propagation of secondary oxidants
Substrate manipulation
Xanthine oxidase inhibitorsAntioxidant enzymes
Radical scavengers
IronCalciumGlucose
Allopurinol; Oxypurinol
SOD, Catalase, Glutathione,
N-AcetylcysteineDMSO, DMTU, 21-
Aminosteroids-Tocopherol
Deferoxamine; calcium blockers
?Increase glucose stores
Approach
(Contd…)
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Blockade of secondary metabolites or inflammatory mediators
Blockade of coagulation effects
Inhibition of excitatory amino acids
Enhancing endogenous antioxidant capability
PAFPhospholipases
Neutrophils
Block platelet adhesionGlutamate receptor
(NMDA) antagonistsRegulon regulation
PAF antagonists Phospholipase inhibitors (quinacrine, hydrocortisone)Selection blockers Reduce activation Block adhesionPAF receptor blockers
Magnesium; MK 801
POTENTIAL THERAPEUTIC STRATEGIESTarget CompoundsApproach
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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
Risk of Death
Risk of Severe disability
61%
72%
5.6%
20%
Mild
< 1%
< 1%
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FUTURE DIRECTIONS
No single magic bullet agent
Multitier combination therapies
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& THE FINAL R…
Thank you
RELAX