PERINATAL ASPHYXIA – PATHOPHYSIOLOGYICAL PARADOX AND

RECENT TRENDS IN MANAGEMENT

Dr Varsha Atul shah

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

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

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%

ETIOLOGY

Intrapartum or Antepartum (90%) Placental Insufficiency

Post partum (10%) Pulmonary Cardiovascular Neurologic Insufficiency

FACTORS Mat. Oxygenation

Blood flow mother to placenta

Blood flow placenta to fetus

Gas Exchange across placenta or fetal tissue

Fetal O2 Req.

PATHOPHYSIOLOGYHypoxia

Diving seal reflex

Shunting of blood to brain adrenals & heart

Away from lungs, kidney gut & skin

NON BRAIN ORGAN INJURYNON BRAIN ORGAN INJURY

PATHOPHYSIOLOGYAsphyxia continues

Shunting within the brain

Anterior Circulation

Suffers

Posterior Circulation Maintained

CEREBRAL CORTICAL LESIONSCEREBRAL CORTICAL LESIONS

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

PATHOLOGY

Target organs of perinatal asphyxia

Kidneys 50%

Brain 28%

Heart 25%

Lung 23%

Liver, Bowel, Bone marrow < 5%

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

PATHOLOGY

Cerebral O2

Substrate supply

Synaptic inactivation (Reversible)

Energy failure

Memb. pump failure

Further in perfusion

At cellular level

ISCHEMIA-RELATED GENERATION OF HYPOXANTHINE

I

S

C

H

E

M

I

A

ATP

AMP

Adenosine

Inosine

Hypoxanthine

ISCHEMIA AND REPERFUSION INJURYIschemia ATP

depletionCalcium influx

Phospholipase activation

Arachidonic acid release

Prostaglandins Proteases, lipases

Vasodilation

Microvascular permeabilityReperfusion

ROS ReleaseROS Release

MECHANISM

RESUSCITATION ATP ASPHYXIA

HYPOXANTHINE

XANTHINE

URIC ACID

Oxygen

Oxygen free radicals

Oxygen

Oxygen free radicals

BLOCKED

BLOCKED

FREE RADICAL

Unpaired

Highly reactive

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

HIE

Glutamate release

Glutamate release

NMDA receptorNMDA receptor

Ca Accumulation In neurones

Ca Accumulation In neurones

Neurtoxicity in HIENeurtoxicity in HIE

NeurotoxicNeurotoxic

CLINICAL MANIFESTATIONS OF HIE

Altered consciousness

Tone problems

Seizure activity

Autonomic disturbances

Abnormalities of peripheral and stem reflexes

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.

SPECIFIC MANAGEMENTPREVENT FURTHER BRAIN DAMAGE

Maintain temperature, perfusion, oxygenation & ventilation

Correct & maintain normal metabolic & acid base milieu

Prompt management of complications

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

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

Communication F - Followup

SUPPORTIVE CARE

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

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

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.

PERFUSIONCFT deranged

Maintain MAP to maintain CBF

Maintain CVP 5-8mm Hg – Term3-5mm Hg –

Preterm

Avoid Fluid, Colloid & SBC Boluses

Replace volume slowly

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

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…)

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

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

HIE OUTCOME (METAANALYSIS)

Severe Moderate

Risk of Death

Risk of Severe disability

61%

72%

5.6%

20%

Mild

< 1%

< 1%

FUTURE DIRECTIONS

No single magic bullet agent

Multitier combination therapies

& THE FINAL R…

Thank you

RELAX