1. PERINATAL ASPHYXIA –
PATHOPHYSIOLOGYICAL PARADOX AND
RECENT TRENDS IN MANAGEMENT
Dr Varsha Atul shah

2. PERINATAL ASPHYXIA
q Insult to the fetus / Newborn
± Lack of oxygen (Hypoxia)
± Lack of perfusion (Ischemia)
q Effect of hypoxia & Ischemia inseperable
q Both contribute to tissue injury

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

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

5. ETIOLOGY
q Intrapartum or Antepartum (90%)
± Placental Insufficiency
q Post partum (10%)
± Pulmonary
± Cardiovascular
± Neurologic Insufficiency

6. FACTORS
↓ Mat.
Oxygenation
↑ Fetal O2 Req. ↓ Blood
flow mother
to placenta
↓ Gas Exchange
across placenta ↓ Blood flow
or fetal tissue placenta to
fetus

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

8. PATHOPHYSIOLOGY
Asphyxia continues
Shunting within the brain
Anterior Posterior
Circulation Circulation
Suffers Maintained
CEREBRAL CORTICAL LESIONS

9. PATHOPHYSIOLOGY
q Near total asphyxia
± Cord accidents
± Maternal CP arrest
q Hypoxia – ABRUPT & SEVERE
± No time for compensation
THALAMUS & BRAIN STEM INJURY, CORTEX SPARED

10. PATHOLOGY
q Target organs of perinatal asphyxia
± Kidneys 50%
± Brain 28%
± Heart 25%
± Lung 23%
± Liver, Bowel, Bone marrow < 5%

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

12. PATHOLOGY
At cellular level
Cerebral O2 ↓
Substrate supply ↓
Synaptic inactivation (Reversible)
Further ↓ in perfusion
Energy failure
Memb. pump failure

13. ISCHEMIA-RELATED GENERATION OF
HYPOXANTHINE
I ATP
↓
S ↓
C AMP
↓
H ↓
Adenosine
E ↓
↓
M
Inosine
I ↓
↓
A Hypoxanthine

14. ISCHEMIA AND REPERFUSION INJURY
Ischemia ATP Calcium influx
depletion
Phospholipase activation
Arachidonic acid release
Prostaglandins Proteases, lipases
Vasodilation
Microvascular
Reperfusion permeability
ROS Release

15. MECHANISM
RESUSCITATION ATP ASPHYXIA
Oxygen HYPOXANTHINE
Oxygen free radicals BLOCKED
XANTHINE
Oxygen BLOCKED
Oxygen free radicals URIC ACID

16. FREE RADICAL
q Unpaired
q Highly reactive

17. EFFECT OF ROS
ROS
DNA strand Lipid Neutrophil accumulation
breakage peroxidation
Release of
Membrane PMN
proteases,
damage plugging of
myeloperoxidase,
capillaries
prostaglandins Phagocytosis
Cell death Ischemia
Tissue damage

18. HIE
↑ Glutamate
release
NMDA receptor Neurotoxic
Ca Accumulation
In neurones
Neurtoxicity in HIE

19. CLINICAL MANIFESTATIONS OF HIE
q Altered consciousness
q Tone problems
q Seizure activity
q Autonomic disturbances
q Abnormalities of peripheral
and stem reflexes

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

21. SPECIFIC MANAGEMENT
PREVENT FURTHER BRAIN DAMAGE
q Maintain temperature, perfusion,
oxygenation & ventilation
q Correct & maintain normal metabolic
& acid base milieu
q Prompt management of complications

22. SUMMARY OF INITIAL MANAGEMENT
q Admit in newborn unit
q Maintenance of temp
q Check vital signs
q Check hematocrit, sugar, ABG, electrolyte
q I.V line
q Consider vol. expander
q Vit K, stomach wash, urine vol

23. SUPPORTIVE CARE
q TABCFMFMCF
q T - Temperature
q A - Airway
q B - Breathing
q C - Circulation
q F - Fluid
q M - Medications
q F - Feed
q M - Monitoring
q C - Communication
q F - Followup

24. SUBSEQUENT MANAGEMENT
q Oxygenation & ventilation
q Adequate perfusion
q Normal glucose & calcium
q Normal hematocrit
q Treat seizure

25. TREATMENT OF SEIZURES
q Correction of hypoglycemia, hypocalcemia &
electrolyte
q Prophylactic Phenobarbitone ?
q Therapeutic Phenobarbitone
20 mg / kg (loading), 5 mg / kg / d (maintenance)
q Lorazepam – 0.05 – 0.1 mg / kg
q Diazepam to be avoided

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

27. PERFUSION
CFT deranged
q Maintain MAP to maintain CBF
q Maintain CVP 5-8mm Hg – Term
3-5mm Hg – Preterm
q Avoid Fluid, Colloid & SBC Boluses
q Replace volume slowly

28. SUPPORTIVE CARE (RECENT ADVANCES)
q Role of Mannitol, Steriod & Hyperglycemia ??
q Regulatory gene (Regulon)
q Hypothermia
q Pentoxifylline
q Enhancement of natural defence
- Neurotrophic factor & fibroblast growth factor

29. POTENTIAL THERAPEUTIC STRATEGIES
Approach Target Compounds
Blockade of free- Xanthine oxidase Allopurinol; Oxypurinol
radical generation inhibitors
Scavenging of Antioxidant SOD, Catalase,
oxidants after enzymes Glutathione,
generation N-Acetylcysteine
Radical scavengers DMSO, DMTU, 21-
Aminosteroids
Blocking chain α-Tocopherol
propagation of
secondary oxidants
Substrate Iron Deferoxamine;
manipulation Calcium calcium blockers
Glucose ?Increase glucose
stores
(Contd…)

30. POTENTIAL THERAPEUTIC STRATEGIES
Approach Target Compounds
Blockade of secondary PAF PAF antagonists
metabolites or Phospholipases Phospholipase
inflammatory mediators inhibitors
(quinacrine,
hydrocortisone)
Neutrophils Selection blockers
Reduce activation
Block adhesion
Blockade of coagulation Block platelet PAF receptor blockers
effects adhesion
Inhibition of excitatory Glutamate receptor Magnesium; MK 801
amino acids
Enhancing endogenous (NMDA)
antioxidant capability antagonists
Regulon regulation

31. PREDICTORS OF POOR
NEURO DEVELOPMENTAL OUTCOME
q Failure to establish respiration by 5 minutes
q Apgar 3 or less in 5 mts
q Onset of Seizure in 12 hrs
q Refractory convulsion
q Stage III HIE
q Inability to establish oral feed by 1 wk
q Abnormal EEG & failure to normalise by 7
days of life
q Abnormal CT, MRI, MR spectroscopy in
neonatal period

32. HIE OUTCOME (METAANALYSIS)
Severe Moderate Mild
Risk of Death 61% 5.6% < 1%
Risk of Severe 72% 20% < 1%
disability

33. FUTURE DIRECTIONS
q No single magic bullet agent
q Multitier combination therapies

36. & THE FINAL R…
RELAX
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