Danylo Halytskyy L’viv National Medical University

Ministry of Health of Ukraine

Guidelines
for Workshops on Paediatrics (Module 2)
for medical students of the 5th year

Topic “Perinatal asphyxia”

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City of Lviv – 2009

Topic: Perinatal Asphyxia

Subject: Paediatrics
Faculty: Medical
# of teaching hours: 4

1. INTRODUCTION

 The incidence of perinatal asphyxia on the West is about 1.0 to 1.5% in most centers and is
usually related to gestational age and birth weight.
 It occurs in 9% of infants less than 36 weeks' gestational age and in 0.6% of infants more than
36 weeks' gestational age, accounting for 20% of perinatal deaths (or as high as 50% of deaths
if stillborns are included).
 The incidence is higher in term infants of diabetic or toxemic mothers; these factors correlate
less well in preterm infants.
 In both preterm and term infants, intrauterine growth retardation and breech presentation are
associated with an increased incidence of asphyxia. Postmature infants are also at risk.
 Up to 10% of CP cases could be connected with perinatal asphyxia.
 Evaluation and care of pregnant women at risk, prevention of fetal hypoxia, and prompt
appropriate resuscitation of newborn at delivery are crucial.

Overall objective – to be able to diagnose perinatal asphyxia, develop a plan for

investigation, treatment and rehabilitation of the infant with perinatal
asphyxia.

2. OBJECTIVES

Knowledge:

- Definition and essential characteristics of perinatal asphyxia;

- Etiology, risk factors аnd pathophysiology of perinatal asphyxia;
- Principles of diagnosis and treatment of fetal hypoxia and asphyxia;
- Apgar score and current recommendations for its usage;
- Clinical signs of HIE and damage of other internal organs;
- Principles of medical care of the baby with perinatal asphyxia;
- Principles of follow up care for infants with HIE..

Performance:

- To make a diagnosis of perinatal asphyxia based on the history, clinical data, and
results of instrumental/laboratory investigations;
- Develop a plan for instrumental/laboratory investigations to confirm the diagnosis of
“perinatal asphyxia”;
- Develop a treatment plan for the newborn with confirmed diagnosis of perinatal
asphyxia;
- Develop a follow up plan for the newborn who survived perinatal asphyxia.

3. MATERIALS FOR SELF-STUDY PREPARATION

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3.1. Prerequisites

Subjects Knowledge Performance

Biochemical markers of hypoxia. To evaluate the results of
Biochemistry
Blood gas analysis. biochemistry blood investigation
Physiology of respiratory and cardiac
Physiology
systems. Classification of hypoxia.
Physiology of newborns,
Pediatrics
peculiarities of transition.
Main causes of perinatal hypoxia
Approach to the prevention,
To diagnose and treat fetal
Obstetrics diagnosis and treatment of fetal
hypoxia
asphyxia.

3.2. Topic content

What is asphyxia?

Even Webster’s dictionary suggests biochemical and clinical evidence are

necessary

Even today the concept…, “Birth asphyxia is a major cause of Cerebral palsy (CP)
and Mental Retardation is common in textbooks in Obstetrics, Pediatrics and
Neonatology.
In western industrial nations CP in term infants is 1-2 / 1000 live births in 1970
and also in 1990.
This is with electronic fetal monitoring (EFM), amnioinfusion, ultra sound, and an
increase in cesarean deliveries from 5 to 25%. No more than 10% of CP (and
even less for retardation) is caused by Perinatal asphyxia. Even if there was
asphyxia in a specific case that may not be the cause of CP, e.g. intrapartum
infection with fetal distress can cause asphyxia but the infectious process may
cause the brain damage.

A task force was set up by the World Federation of Neurology Group for the prevention of cerebral
palsy and related neurologic disorders to discuss the term "birth asphyxia" and its appropriate use. It
was recommended that the term perinatal asphyxia and hypoxic-ischemic encephalopathy should
not be used until or unless some evidence specific to the asphyxial origin for neurologic illness in
the neonate is available.

The aim of this recommendation was to encourage accurate diagnosis. Specific evidence of
asphyxia can be provided by means of a blood gas and acid-base assessment. When this is achieved,
an accurate determination of the timing of asphyxial insult is important. Thus the term birth
asphyxia should not be used. The effects of fetal asphyxia resulting from compromised maternal-
fetal blood gas exchange before delivery should be differentiated from newborn asphyxia resulting
from cardiorespiratory complications after delivery. Accurate diagnosis and precise timing are
essential if strategies to prevent or modify the effects of asphyxia are to be developed.

The Task Force defined asphyxia as a condition of impaired gas exchange leading, if it persists, to
progressive hypoxemia and hypercapnia. This is a good definition of asphyxia as it may affect the
fetus and newborn. However this may occur in a transient fashion that, although of physiological
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interest, has no pathologic significance. Significant asphyxia leading to tissue oxygen debt with
accumulation of fixed acids results in a metabolic acidosis. Thus for clinical purposes the following
addition is proposed to this definition: Perinatal asphyxia is a condition of impaired blood gas
exchange leading to progressive hypoxemia and hypercapnia with a significant metabolic acidosis.

There is a growing body of evidence from laboratory and clinical studies that the threshold for a
significant metabolic acidosis is a base deficit between 12 and 16 mmol/L. Asphyxia with a
significant metabolic acidosis is associated with seizures in the fetal lamb. Clinical studies have
demonstrated an association between severe acidemia and multiorgan complications in the
newborn. This association with newborn complications occurs with a severe metabolic acidosis but
not with a respiratory acidosis.

Routine blood gas and acid-base assessment of umbilical artery blood at delivery has demonstrated
an umbilical artery base deficit > 12 mmol/L in 2% and > 16 mmol/L in 0.5% of the total
population. Such an assessment confirms that 98% of newborns do not have a significant asphyxial
episode during labor and delivery. However, 2% have been exposed to asphyxia, which may affect
their outcome.

Evidence of a significant metabolic acidosis can establish that exposure to asphyxia has occurred.
This will also indicate the degree of metabolic acidosis at the time of sampling. However, it does
not necessarily reflect the severity of the asphyxial exposure to the fetus. The duration of the
hypoxia is generally not known. The nature of the insult (i.e., continuous or intermittent) or whether
the asphyxia during labor and delivery is the last of a series of episodes is not known.
The importance of an asphyxial exposure is influenced by the fetal response. This response is a
centralization of the fetal circulation with increased blood flow to the brain, heart, and adrenals.
However, if the hypoxia is sustained, fetal cardiovascular decompensation will occur. Laboratory
studies in the fetal lamb have demonstrated decreased cerebral blood flow and cerebral oxygen
metabolism and brain damage as a result of fetal cardiovascular decompensation. These studies
have also demonstrated that the fetal response is not necessarily proportional to the exposure.
A classification of the severity of an asphyxial exposure is required to predict the long-term
outcome in the child. This is important for the 2% of newborns who have been exposed to an
asphyxial event. The majority of these events will be mild or moderate, with results of little short-
or long-term significance.

The severity of intrapartum fetal asphyxia can be classified by determining the short-term outcome
as expressed by newborn encephalopathy and other newborn organ system complications. This
alternative is required because the duration of the asphyxia itself cannot be determined and the
clinical measures of fetal cardiovascular compensation and decompensation are not available.
Additionally, the vulnerability to the exposure may depend on the different characteristics of the
fetus (i.e., gestational age, small for gestational age vs appropriate for gestational age). A
classification of mild, moderate, and severe intrapartum fetal asphyxia is presented in Table I.

Table I
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Classification of perinatal asphyxia

The following criteria have been used in our program to classify newborn complications. The
clinical signs of newborn encephalopathy associated with intrapartum fetal asphyxia occur more
often on day 1 after delivery, with decreasing frequency on day 2 and 3. Newborn encephalopathy
was classified as minor if it consisted of jitteriness and irritability, moderate if it consisted of
lethargy or abnormal tone, and severe if it consisted of coma or abnormal tone and multiple
seizures. Cardiovascular complications were classified as minor if there was bradycardia or
tachycardia (defined by the 95% confidence limits for heart rate for term and preterm newborns),
moderate if there was hypertension or hypotension (defined by the 95% confidence limits for blood
pressure for term and preterm newborns), and severe if there was abnormal electrocardiographic or
echocardiographic findings. Respiratory complications were classified as minor if requiring
supplementary oxygen, moderate if requiring continuous positive airway pressure or transient
ventilation (< 24 hours), or severe if requiring mechanical ventilation for > 24 hours. Renal
complications were classified as minor if hematuria was observed, moderate if there was an
elevation of serum creatinine (> 100 micro mol/L), and severe with clinical evidence of oliguria (<
1 ml/kg/hr) or anuria.

II. ESSENTIAL CHARACTERISTICS OF PERINATAL ASPHYXIA

A. Profound metabolic or mixed acidemia (pH <7.00) on an umbilical cord

arterial blood sample.
B. Persistence of an Apgar score of 0 to 3 for more than 5 minutes
C. Clinical neurologic sequelae in the immediate neonatal period to include
seizures, hypotonia, coma, or HIE.
D. Evidence of multiorgan system dysfunction in the immediate
neonatal period.

III. CAUSES - Five principle causes:

A. Interruption of umbilical circulation (cord compression/accidents)
B. Altered placental gas exchange (abruption, previa, insufficiency)
C. Inadequate perfusion of maternal side of placenta (↓ BP, ↑ BP, abnormal
uterine contractions)
D. Impaired maternal oxygenation (Heart disease, Anemia)
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E. Failure of fetus to successfully establish neonatal cardiopulmonary

circulation.

IV. PATHOPHYSIOLOGY
A. Redistribution of blood to heart, brain, and adrenals.
B. ↓ pO2 and ↑ pCO2 stimulate cerebral vasodilation
C. Preferential ↑ in CBF to brainstem early and reduction later
D. Loss of cerebral autoregulation
E. Reduced cardiac output: hypotension
F. ↓ metabolic rates and ↑ glycogen help the fetus withstand longer periods of
asphyxia
G. Adenosine, GABA, opiates are released, these help to reduce O2
consumption.

V. CLINICAL EVENTS
A. The initial response is hypertension and tachypnea, followed by
primary apnea, then gasping attempts to breathe.
B. Unresolved hypoxia leads to secondary apnea, bradycardia, and
shock.
C. Diminished cerebral blood flow and loss of oxygen supply results in
vessel injury.
D. Cerebrovascular injury leads to cerebral edema.
E. Cerebrovascular hemorrhage occurs upon reperfusion of ischemic
and damaged areas of the brain. However, following prolonged and severe
asphyxia, local tissue recirculation may not be restored upon
reoxygenation due to collapsed capillaries in the presence of severe
cytotoxic edema.

VI. MECHANISMS OF DAMAGE

A. Irreversible Cellular Injury - Following prolonged HII > 30 minutes, some

cells do not recover, plasma membranes suffer severe osmotic
stresses/biochemical damage caused by free radicals or Ca-activated
phospholipases. Pretreatment with GM1 ganglioside (a component of
plasma membranes) protects against HIE. Facilitating recovery of neurons
immediately reduces irreversible damage and improves outcome.

B. Reperfusion - There is a period of increased perfusion after

circulation is restored with reoxygenation after HIE. Acute
cytotoxic edema resolves in 30 minutes.

C. No-Reflow Phenomenon
1. When tissue perfusion is not restored after severe HIE with
reoxygenation, the no-reflow phenomenon is said to exist.
2. Early cerebral edema is cytotoxic/intracellular
- it is in the gray matter
- it resolves in 1 hour
- it collapses capillaries and obstructs reperfusion.
3. Secondary edema occurs hours after primary insult due to increased
capillary permeability and ↑ fluid in the ECF.
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4. Calcitonin gene related peptide seen around infarcted developing

brain is partly responsible for ↑ vascular permeability and vasogenic
edema. ICF maximizes around 36-72 hours after HIE insult.
5. Mannitol etc. may ↓ brain H2O but does not improve outcome.

D. O2 Free Radicals
1. Theoretical protection offered by: scavengers-
cholesterol, vitamin C, glutathione, SOD, glutathione
peroxidase, catalase and allopurinol treatment.
2. Can trigger hypoperfusion in the fetal brain by
stimulating leukotriene production and producing
leukocyte clumps which plug up capillaries.
3. Post asphyxial depression, hypotonia and EEG suppression is caused
by adenosine, opiates and GABA - all inhibitory neuromodulators.
4. Additional insults worsen outcome.
5. If the depressive phase is prolonged it usually means a poor
outcome.

E. The several outcomes include:

1. Selective neuronal loss (not involving glial cells) located in the
cortex and hippocampus without any clinical features such as
seizures or edema.
2. Secondary deterioration with seizures, edema, and infarction in
some infants.
3. Microglia becoming activated macrophages produce,
excitatory amino acid glutamate, H2O2 and glial toxins which produce
further damage.
 Hypoxemia ASPHYXIA Hypercarbia

Anaerobic Glycolysis Dilation of cerebral vessels

Increased glucose consumption Increased glucose delivery

Excessive lactate production

Mixed acidosis

Disturbance of Loss of cerebral Impairment

glycolytic autoregulation of miocardial function
processes
Diminished cardiac output

LOCAL HYPOXIC-ISCHEMIC INSULT

Depletion of local glucose stores Excessive lactate production

↑ Metabolic acidosis
Energy failure

Impairment of cellular ion pumps

Ionic shifts and membrane depolarization

Intracellular (early)cerebral Excitotoxic amino acids release

edema (neurotransmitters – glutamate, aspartate etc.)

N-mеthyl-D- aspartate (NMDA) receptors

Opening of ion (Na+, Cl-) channels Activation of Са2+-dependent channels

Ions (Na+, Cl-) get into the cells Excessive Са2+ intracellular influx

Immediate neuronal death Activation of Са2+-dependent lipases

and proteases;
Perturbation of mitochondrial
respiratory electron chain transport;
Generation of free radicals and
leucotriens;
Depletion of energy stores.

Delayed neuronal death

Scheme 1. Pathogenesis of Perinatal Asphyxia

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VII. FACTORS THAT INFLUENCE OUTCOME

A. Metabolic
1. - Glucose status - controversial.
↑ sugar toxic to growth retarded fetus.
- Postnatal animals treated with glucose withstand longer
periods of
asphyxia.
2. - Severe lactic acidosis worsens outcome in developing
brain.
- However acidosis suppresses excitatory receptors and
protects
developing neurons against hypoxia.
- Acidosis is also protective for developing heart.
- High levels (> 18 mM) of lactic acid cause infarction.
B. Gestational Age - VLBW: poor prognosis
C. - PVL leading to spastic diplegia or hemiplegia.
- There is a 27 times greater risk of morbidity if asphyxia occurs
after 38 weeks gestation.
- Term infants parasagittal cortex - vulnerable.
D. Umbilical cord occlusion - Cord occlusion of > 10 minutes causes
brain injury.
E. Seizures that last > 30 minutes - poor outcome

F. Repetitive Injuries
1. Intermittent cord compression secondary to olgohydrammois can
result in cerebral palsy.
2. Experimental studies show that repeated insults at 1 hour interval
→ striatal damage and sensitize fetal brain to damage.
G. Growth Retarded fetuses are
1. More susceptible, and they have a reduced ability to adapt to
asphyxia.
2. ↓ fetal heart rate variability due to chronic stress and sympathetic
stimulation.

VIII. FETAL ASPHYXIA

A. Prevention of Fetal Asphyxia
1. Team Approach - Perinatologist
- Anesthesiologist
- Neonatologist/Pediatrician
- Neonatal Resuscitation Team
- Transport Team
In all situations where the delivery is not imminent:
The neonatologist is consulted prior to the birth of the infant, the
case is discussed by the neonatologist/pediatric team with the
perinatologist / OB team and plans for delivery are discussed.
Neonatologist/Pediatric team clearly outlines plan of management
for the infant and shares the information with family.

2. Identify the Fetus at Risk

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Current Pregnancy conditions: Hypertensive

Multifetal gestation
Late prenatal care
Decreased fetal groqth
Decreased movement
Lupus
Active medical problems
 42 weeks
Cholestatis
Placental problems
Blood group incompatibility

Historical: Medical problems

Low birthweight
Stillbirth
Toxemia
Diabetes
Drug abuse
Pyelonephritis

3. Recognition of Fetal - Monitoring in labor

Asphyxia
- Fetal movements/kick sheet - Fetal Blood Flow
- Growth - Fetal Blood Gas
- Biophysical Assessment a. Cardiocentesis
- Amniotic fluid volume b. Fetal Scalp Sampling
- Meconium c. Transcutaneous
- EFM (Electronic Fetal Monitoring) SaO2 and PaO2
- Non Stress Test d. NIRS (Nieroscopy)

Electronic Fetal Monitoring does not necessarily offer a

benefit as compared to Auscultation.

No benefit shown in 50,000 + low and high risk patients studied, both in
perinatal mortality, morbidity, Apgar score, cord blood gases and long term
outcomes (“Dublin Study”).
“Within specified intervals, intermittent auscultation is equivalent to
continued FHR monitoring in detecting compromise”. Fetal Heart Rate
Monitoring, ACOG Bulletin, 132. 1989)… BUT CURRENT DATA DO IDENTIFY THE
VALUE OF ELECTRONIC FETAL MONITORING.
Table 2
Fetal Scalp pH

pH value INTERPRETATION ACTION

>7.25 Reassuring Repeat if FHR pattern changes
7.25-7.15 Ominous Repeat in 15 minutes
<7.15 Asphyxia Deliver in 15 minutes

Fetal/Newborn Blood Gas

Fetal Umbilical Gas
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Age Vessel PO2 pH PCO2

Artery 10-20 mm Hg 7.20-7.28 45-55 mmHg
Fetal
Vein 25-35 mmHg 7.28-7.36 35-45 mmHg
At birth (10
Artery 50 mm Hg 7.21 46 mmHg
min)

5 hours Artery 74 mm Hg 7.34 35 mmHg

Table 3
Treatment of Acute Fetal Asphyxia
GOAL METHOD
Relieve cord compression Elevate presenting part
Relax uterus
Amnioinfusion
Maximize oxygen delivery Give maternal O2
Maximize uterine perfusion Position to avoid caval compression
Expand maternal blood volume
Relax uterus
Give maternal inotropic agents

Table 4
Treatment for Chronic Fetal Asphyxia
PROBLEM METHOD

Fetal anemia Transfusion, intraperitoneal or intravascular

Fetal tachyarrythmia Digitalis, antiarrhythmics
Lupus anticoagulant Glucocorticoids, heparin, aspirin
Three or more fetuses Pregnancy reduction
Twin-twin transfusion Fetal removal
Growth retardation Rest, oxygen, beta-agonists, aspirin
Recurrent toxemia with IUGR Aspirin plus dipyramidole

IX. ACIDOSIS AND OUTCOME

Severe neonatal acidosis → good neonatal course (neurologic) → good neonatal outcome
Severe neonatal acidosis → bad neonatal course (neurologic) → bad neonatal outcome

900 children with Umbilical artery gases done → 4 children had CP

AND all umbilical artery gases showed a pH > 7.0
In fact it is believed by some that the normal range of umbilical artery pH should be
7.10 – 7.15
Since 7.0 – 7.2 shows no correlation with immediate or long-term morbidity.
And < 7.0 represents clinically significant acidosis

A. 10 - 30% of deliveries have meconium in amniotic fluid

Only 5% may have associate significant acidosis.

B. Neonatal Acidosis - does not lead to poor neurological outcome

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Most studies have found not meaningful correlation between

problematic pH/ base excess and outcome.

X. APGAR SCORES AND OUTCOME

A. Low Apgar Scores NOT synonymous with terms hypoxia, acidosis, or asphyxia.
B. The Apgar score quantifies and summarizes the response of the newly born infant
to the extrauterine environment and to resuscitation. Each of the five signs is
awarded a value of 0, 1, or 2. The five values are then added and the sum
becomes the Apgar score.

Score
Sign
0 1 2

Heart rate Absent Slow (<100 beats/min) >100 beats/min

Respirations Absent Slow, irregular Good, crying

Muscle tone Limp Some flexion Active motion

Reflex irritability (catheter in
No response Grimace Cough, sneeze, cry
nares, tactile stimulation)
Pink body, blue
Color Blue or pale Completely pink
extremities

C. Factors affecting Apgar Score other than depression from asphyxia

1. Gestational Age
2. Maternal Medication
3. Infection
4. Neuromuscular disorders
5. Cardiopulmonary disease at birth
6. Inconsistency of scoring
7. No clocks
8. No one pushes the clock
9. Observer / scorer and resuscitator are all one

D. Apgar scores should be assigned at 1 and 5 minutes after birth. When the 5-minute score
is less than 7, additional scores should be assigned every 5 minutes for up to 20 minutes.
These scores should not be used to dictate appropriate resuscitative actions, nor should
interventions for depressed infants be delayed until the 1-minute assessment.
The scores should be recorded in the baby's birth record. Complete documentation of the
events taking place during resuscitation must also include a narrative description of
interventions performed and their timing.

E. Apgar score 0-3 at 15 minutes - CP in 10%

at 20 minutes - CP in 60%
Nelson & Ellenberg, Ped, 68:36, 1981

Between 25-75% of infants with severe acidosis have normal Apgar scores.
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F. Diagnostic value of low Apgar score in identifying Asphyxiated infants

is
NIL

C. Persistent low Apgar score (0-3) at 10, 15, and 20 minutes has a
fairly good relationship to long term outcome and also indicates an
increased risk of death (60% in term and 50-100% in <1500 gram
infant)

H. APGAR SCORE 0 AT 1 MINUTE

93 Resuscitated
↓
62 (66%) Responded
↓
36 Discharged from NICU
↓
33 Alive at 1 year
↓
23 (Available for follow up)

Abnormal Normal Suspect

6 14 (15%) 3

Jain, et al., JPed 118; 778, 1991.

XI. CLINICAL FEATURES OF NEONATAL HYPOXIC-ISCHEMIC

ENCEPHALOPATHY (Sarnat and Sarnat classification)

A. First 12 to 24 hours: An apparent hyperalertness or

hyperexcitability, seizures, apnea, jitteriness, weakness.

24 to 72 hours: Obtundation or coma; ataxic respirations with

subsequent respiratory arrest; abnormal oculomotor reflexes; impaired
pupillary response; intracranial hemorrhage (prematures) with
subsequent deterioration.

Beyond 72 hours: Persistent stupor; abnormal or absent sucking,

swallowing, and gag reflexes which impair feeding; generalized
hypotonia; weakness.

B. Severity of HIE and Outcome

Outcome
Severity Features (%
abnormal)
Hyperalert, jittery, Exaggerated Moro and 0
Mild Stretch reflexes, Duration < 24 hours.
Lethargy/Stupor, hypotonia, suppressed 20-40
Moderate
reflexes, seizures.
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Coma, hypotonia, seizures, abnormal

Severe brainstem and autonomic function, ↑ ICP, 100
Apparent ↑ in alertness 12-24 hours.

C. Seizures with HIE

Associated with:
33% - mortality
55% - cerebral palsy
Risk of neurological sequelae - 5-fold increase

EEG patterns of prognostic significance

Associated with normal outcomes: Mild depression (or less) on day 7
Normal background by day 7

Associated with poor outcome: Burst suppression pattern on any

day
Isoelectric tracing on any day
Mild (or greater) depression after day 12.
D. Multiorgan dysfunction
Infants with neonatal encephalopathy alone not involving other organs
are unlikely to
have asphyxia as their causative factor.

1. CNS: Hypoxic-ischemic encephalopathy, cerebral edema, IVH,

PVL, seizures, long-term neurologic sequelae
2. Pulmonary: Pulmonary hypertension, surfactant disruption,
meconium aspiration, pulmonary hemorrhage
3. Renal: Oliguria, acute renal failure, acute tubular necrosis,
acute cortical necrosis,
4. Cardiovascular: Tricuspid insufficiency, myocardial necrosis,
shock/ hypotension
5. Metabolic: Metabolic acidosis, hypoglycemia, hypocalcemia,
hyponatremia
6. Gastrointestinal: Necrotizing enterocolitis, hepatic dysfunction
7. Hematologic: Thrombocytopenia, disseminated intravascular
coagulopathy
8. Death

XII. INVESTIGATIONS

A. Biochemical Indices

1. ↑Acidemia (Respiratory, metabolic, mixed)

2. ↑ Base Excess (-20 mEq/L) (normal 6.0 to 10 mEq/L)
3. ↓ pH (< 7.00) (mixed or metabolic up to 7.10 to 7.15 may be normal)
4. β -2 microglobulin - renal tubular damage
5. CPK - BB and MB
6. Lactic Acid
7. Blood & CSF lactate
8. Hypoxanthine
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SGPT, SCOT
EKG
UA, UO, Specific gravity, lytes
CBC, diff, platelets, PT, PTT
serum osmolality
EEG
ECHO heart
Ultrasound
MRI
CT scan
SPECT
PET
VEP: visual evoked potentials
SEP: somatosensory evoked potentials

B. CLASSIFICATION OF CRANIAL ULTRASOUND FINDINGS

Acute Phase Late Phase

I No abnormalities No abnormalities
II Transient increase (>48 hr) in periventricular No abnormalities or slightly pronounced
echogenicity ventricles
III Diffuse increase in periventricular and/or Periventricular and/or (sub)cortical cysts in
(sub)cortical echogenicity survivors or severe atrophy
Increased thalamic echogenicity
Persisting thalamic echogenicity
Middle cerebral artery infarct (confirmed by CT
Atrophy of ipsilateral ventricle and
or MRI)
cystic degeneration

XII. CEREBRAL PALSY

In the West:
⋅ rate of CP is 1-2/1,000 births,
⋅ now and 20 years ago despite changes in C-sections from 5-25%
and Electronic fetal monitoring
Only 6-10% of CP is associated with asphyxia as defined by acidosis,
decreased Apgar score and clinical sequelae.
In infants with low 10 minute Apgar scores, congenital disorders are
more common than asphyxia in both quadraplegic and non-
quadraplegic CP.
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Even if asphyxia is identified, CP does not always result.

XIII. SCORING TO PREDICT OUTCOME

Post Asphyxia Morbidity

Signs Points
0 1 2 3
5 minute Apgar >6 5-6 3-4 0-2
Base deficit (mEq/L) <10 10-14 15-19 >20
Severe Prolonged
Fetal heart rate pattern Normal Variable variables or bradycard
late decels ia
If score is > 6, it indicates severe morbidities; positive predictive value of 88%; negative
predictive value of 73%.
(Postman et al, AJOG, 162:174, 1990)
XIV. TREATMENT
A. Prevention
B. Old but Standard Therapies
1. Fluid restriction, volume
2. Treat seizures
3. Maintain perfusion and BP, use pressors
4. Adequate oxygenation
5. Appropriate ventilation
6. Glucose

As it was already emphasized before, resuscitation in delivery room is of great value. Other
specific management consists of supportive care to maintain temperature, perfusion, ventilation,
and a normal metabolic state, including glucose, Ca2+ and acid-base balance. Control of seizures
is important as well.
(1) О2 levels should be kept in the normal range by monitoring transcutaneous or arterial PO2
or percent 02 saturation by pulse oximeter. Hypoxia should be treated with 02 and/or
ventilation. Hyperoxia also may cause a decrease in CBF or exacerbate free radical damage.
Aminophylline may decrease CBF and should not be used in the initial management of
apnea due to asphyxia.
(2) CO2 should be kept in the normal range because hypercapnia may cause cerebral
vasodilation, which may cause more flow to uninjured areas with relative ischemia to
damaged areas ("steal phenomenon") and extension of infarct size. The excess flow to
uninjured areas may furthermore be associated with ICH because of loss of autoregulation of
CBF. Excessive hypocapnia may decrease CBF. Hyperventilation is not recommended.
(3) Perfusion. It is important to maintain cerebral perfusion pressure (CPP) within a narrow
range. Too little can cause ischemic injury; too much can cause hemorrhage in the areas of
damaged blood vessels, with germinal matrix hemorrhage and IVH in premature infants.
Excessive reperfusion of infarcted tissue may cause the infarct to become hemorrhagic
because of loss of vascular integrity. Abrupt changes in perfusion and rapid infusions of
volume expanders or sodium bicarbonate may be associated with IVH. Because
cerebrovascular autoregulation is lost, cerebral perfusion entirely reflects systemic BP in a
pressure-passive fashion. To maintain cerebral perfusion, a systemic mean arterial BP of at
least 45 to 50 mm Hg is usually desirable for term infants, 35 to 40 mm Hg for infants
weighing 1000 to 2000 gin, and 30 to 35 mm Hg for infants weighing less than 1000 gm.
Conversely, if hypertension develops and persists despite the discontinuation of pressors and
the institution of adequate sedation, the systemic BP should not be lowered further, since it
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may be needed to maintain adequate CPP in the face of increased ICP. The following
recommendations should be adhered to:
(a) Continuously monitor arterial BP. Continuously monitor CVP, if possible, to ensure
there is adequate preload, i.e., that infant is not hypovolemic due to vasodilatation or
third spacing.
(b) Keep systemic mean arterial BP at no lower than 45 to 50 mm Hg in term infants, 35 to
40 mm Hg in 1000- to 2000-gm infants, and 30 to 35 mm Hg in infants weighing less
than 1000 gm. Keep CVP 5 to 8 mm Hg in term infants and 3 to 5 mm Hg in preterm
infants.
(c) Minimize pushes of colloid or sodium bicarbonate, but regularly replace intravascular
volume losses as needed to avoid lactic acidosis.
(d) Give volume replacement slowly.
(e) Minimize administered free H2O (insensible losses plus urine output); however, if urine
output is low, first ensure that intravascular volume is adequate (i.e., rule out prerenal
etiology) before fluid restriction.
(f) Judicious use of pressors may help minimize the need for colloid in maintaining BP and
perfusion.
(g) Monitor ICP if possible.
(4) Glucose. Blood glucose level should be kept at 75 to 100 mg/dl to provide adequate
substrate for the brain. Higher levels may lead to elevation of brain lactate, damage to
cellular integrity, increased edema, and further disturbances in vascular autoregulation.
Lower levels may potentiate excitotoxic amino acids and extend the infarct size.
Hypoglycemia, due both to glycogen depletion secondary to catecholamine release and to
an unexplained hyperinsulinemic state, is often seen in asphyxiated infants. An initial phase
ofAyperglycemia and hypoinsulinemia (5 to 10 minutes following an acute event due to a
catecholamine surge which inhibits insulin release and stimulates glucagon release) may be
followed within 2 to 3 hours by profound /hypoglycemia. Normal glucose infusion rates of
5 to 8 mg/kg per minute may not be sufficient to maintain normoglycemia; rates as
high as 9 to 15 mg/kg per minute may be required for short periods. Because
hypoglycemia may be difficult to control without causing fluid overload, concentrated
glucose infusions may be necessary by means of a central line (e.g., a "high" umbilical
venous line with its tip in the right atrium). Since rapid glucose boluses should be avoided,
serum glucose level should be monitored frequently and adjustments anticipated. Glucose
infusions should be discontinued slowly to avoid rebound hypoglycemia. Seizures may
result from hypoglycemia; therefore, if seizures do occur, the possibility of hypoglycemia
should be ruled out or treated appropriately before reflexly instituting anticonvulsant
therapy (see below). Seizures in such an instance would not be used for Sarnat clinical
staging.
(5) Temperature should be kept in a normal range. While animal studies are promising, deep
hypothermia has not yet proved to be "brain sparing" after asphyxia in humans.
(6) Calcium level should be kept in a normal range. Hypocalcemia is a common metabolic
alteration in the neonatal postasphyxial syndrome. A subnormal serum Ca 2+ level will not
forestall neuronal damage and may only serve to compromise cardiac contractility or cause
seizures.
(7) Seizures. In neonatal HIE, they are typically focal or multifocal (myelinization and
synaptogenesis not having developed sufficiently for generalization of seizures). Seizures
occur in about 50% of infants with HIE in most series, characteristically on the first or
second day, usually in stage 2, only rarely in stage 3, and almost never in stage 1 according
to Sarnat and Sarnat stages. They may be associated with an increased cerebral metabolic
rate, which in the absence of adequate O2 and perfusion may lead to a fall in blood glucose
level, an increase in brain lactate level, and a fall in high-energy phosphate compounds. In
infants not mechanically ventilated, seizures may be associated with hypoxemia and/or
 18

hypercapnia. Abrupt elevations in BP associated with seizures may contribute to ICH in

preterm infants. When seizures are clinically apparent and of typical morphology, an EEG is
not necessary to confirm the diagnosis (though data regarding interictal background activity
may be useful for assessing the overall "well-being" of the brain). In infants paralyzed with
pancuronium for mechanical ventilation, seizures may be manifested by abrupt changes in
BP, heart rate, and oxygenation. An EEG should be obtained in these circumstances.
Whether seizures alone, in the absence of metabolic or cardiopulmonary abnormalities, lead
to brain injury is controversial. While one should have a low threshold for diagnosing
seizures in the setting of HIE, it is no longer thought that asphyxiated infants should be
treated prophylactically with anticonvulsants in the absence of clinical seizures (or electrical
seizures on EEG in the case of an infant pharmacologically paralyzed). There is actually
very little change in ICP during most electrographik seizures. The clinical distinction
between multifocal seizures and the "jitteriness" (actually a rhythmic segmental
myoclonus seen frequently in stage 1 and even stage 2 HIE is often difficul to make by
observation alone. Taking hold of the clonic extremity and changing the tension on the
muscle stretch receptor by slightly flexing or extending the joint immediately arrests clonus
but does not alter true seizure activity, during which rhythm' convulsive movements
continue to be felt in the examiner's hand. When seizures are diagnosed, phenobarbital
should 1 loaded slowly, 20 mg/kg intravenously to be followed by a maintenance dose of
3 to 5 mg/kg per day. One should always be vigilant for respiratory depression and/or
cardiovascular compromise with hypotension. If the infant is already mechanically
ventilated, respiratory depression is not a concern. In non-intensive care unit (ICU) settings,
one may divide the loading dose of phenobarbital or use phenytoin. Phenobarbital,
especially at hi levels, itself can cause lethargy, stupor, and occasionally brain stem signs. If
seizures persist, phenytoin may be administered slowly as a second drug (20 mg/kg
intravenously as a loading dose followed by 4 to 8 mg/kg per day as a maintenance
dose). One should, of course, ascertain that metabolic derangementas that may complicate
asphyxia and cause seizures have been dressed (e.g., hypoglycemia, hypocalcemia, and
hyponatremia). Pyridoxine-dependency seizures and local anesthetic toxicity may
mimic postasphyxic seizures and should be considered in differential diagnosis. If seizures
nevertheless persist, a benzodiazepam (e.g., lorazepam 0.05 to 0.10 mg/kg per dose
intravenously) may be given transiently as a third drug. If vascular access cannot be
achieved in the non-ICU setting, rectal diazepam, valproate, or paraldehyde may provide a
stopgap. (Intramuscular phenobarbital is absorbed too slowly and, because it may confound
subsequent management, its use is discouraged.) Seizures in HIE are notoriously difficult to
control and often resistant to even aggressive anticonvulsant therapy in the early stages (first
72 hours) of the syndrome. Once levels of conventional anticonvulsants are maximized
(phenobarbital level to 40 mg/dl, phenytoin level to 20 mg/dl), unless there is cardiopulmo-
nary compromise from the seizures, there is often little utility or desirability to eliminating
every "twitch" or electrographic seizure. (There is a growing understanding that even status
epilepticus will not extend extant cortical damage or heighten morbidity.) For unexplained
reasons, even refractory seizures in HIE ultimately "burn themselves out" and cease after
approximately 48 hours.
• When the infant's condition has been stable for 3 to 4 days, all anticonvulsants
are weaned except phenobarbital (the level of which may be allowed to drop to 15
to 20 mg/dl if possible).
• If seizures have resolved, if neurologic findings are normal, and if the EEG is normal,
anticonvulsants are stopped in the neonatal period (14 days of life).
• If this is not the case, anticonvulsants are continued for 1 to 3 months. If the
neurologic findings are then normal with no recurrent seizures, phenobarbital is ta-
pered over 4 weeks. If the neurologic results are not normal, the advisability of
 19

continued anticonvulsant therapy requires consideration of the initial cause of the

seizures.
• The risk of subsequent epilepsy is 100% with seizures secondary to cerebral cortical
dysgeneses but only 20 to 30% after seizures secondary to perinatal asphyxia and
essentially nil after seizures secondary to transient metabolic disturbances. Infants
with a higher risk of subsequent seizures are those with a persistent neurologic deficit
(50% risk) and those with an abnormal EEG between seizures (40% risk). If the result
of neurologic examination is not normal, an EEG is obtained; if there is no
electrographic seizure activity, phenobarbital is tapered and discontinued over 4
weeks, even if the infant has abnormal neurologic signs.
(8) Cerebral edema. Devices applied to the anterior fontanel provide noninvasive methods for
measuring ICP. Cerebral edema may be minimized by avoiding fluid overload, although
initial resuscitation of an asphyxiated infant and maintenance of cardiovascular stability and
CPP (CPP = systemic mean arterial BP - ICP) should always take priority. Two processes
may predispose to fluid overload in asphyxiated infants: (1) syndrome of inappropriate
secretion of antidiuretic hormone (SIADH) and (2) acute tubular necrosis (ATN).
SIADH, often seen for 3 to 4 days after the insult, is manifested by hyponatremia and
hypoosmolarity with excretion of an inappropriately concentrated and Na+-containing urine
(elevated urine specific gravity, osmolarity, and Na+). SIADH should be monitored by daily
determinations of serum and urinary Na+ and osmolarity. Urine output may further be
compromised by ATN resulting from shunting of cardiac output away from the kidneys.
Persistent oliguria (<1 ml/kg per hour for the first 36 hours of life) can provide an index of
the severity of asphyxia and risk for neurologic sequelae. To avoid fluid overload and the
exacerbation of cerebral edema, both SIADH and ATN should be managed by
limitation of free H20 administration only to replacement of insensible losses and urine
output (usually <60 ml/kg per day). Before attributing oliguria to SIADH or ATN, rule
out prerenal etiologies (hypovolemia, vasodilation) with a 10 to 20 ml/kg fluid challenge
followed by a loop diuretic if there is no urine output.
Cerebral edema and increased ICP (>10 mm Hg) are actually fairly uncommon
concomitants of perinatal asphyxia. When present, they more often reflect extensive prior
cerebral necrosis rather than swelling of intact cells, and because they bespeak such
extensive cell death, they have a uniformly bad prognosis. They peak 36 to 72 hours after
the insult. They are more properly regarded as an effect rather than a cause of brain damage.
For this reason, efforts specifically to reduce cerebral edema or ICP do not affect outcome;
neither do ICP elevations reduce cerebral perfusion or introduce any acute functional
neurologic disturbances. Therefore, such interventions previously explored in the literature
as antiedema agents (e.g., high-dose phenobarbital, steroids, mannitol, and other hypertonic
solutions) are not employed at our institution. The infant's patent sutures and open fontanel
are protective of any acute increases in ICP that might occur. Our major efforts are
devoted to ensuring an adequate CPP through maintaining an adequate systemic mean
arterial BP, shown in recent studies to be a more important variable than ICP in ensuring
adequate CBF. A simple beside estimate of ICP can be made in infants (assuming no
elevations of CVP such as occurs with pneumothorax or during treatment with continuous
positive airway pressure) by measuring the vertical distance between the anterior fontanel
and the heart, measured at the point that the midportion of the fontanel flattens as the baby is
tilted up. Normal will be 50 mm H2O or lower.

Summary of Post-Resuscitation Care

Organ System Potential Complication Post-Resuscitation Action
 20

Brain Apnea Seizures Monitor for apnea

Support ventilation as needed
Monitor glucose and electrolytes
Avoid hyperthermia
Consider anticonvulsant therapy
Lungs Pulmonary hypertension Maintain adequate oxygenation and
Pneumonia ventilation
Pneumothorax Consider antibiotics
Transient tachypnea Obtain x-ray if respiratory distress
Meconium aspiration syndrome Consider surfactant therapy
Surfactant deficiency Delay feedings if respiratory distress
Cardio- Hypotension Monitor blood pressure and heart rate
vascular Consider inotrope (eg, dopamine) and/or
volume replacement
Kidneys Acute tubular necrosis Monitor urine output
Restrict fluids if oliguric volume and
vascular volume are adequate
Monitor serum electrolytes
Gastro- Ileus Delay initiation of feedings
intestinal Necrotizing enterocolitis Give intravenous fluids
Consider parenteral nutrition
Metabolic/ Hypoglycemia Monitor blood sugar
Hematologic Hypocalcemia; hyponatremia Monitor electrolytes
Anemia Monitor hematocrit
Thrombocytopenia Monitor platelets

(9) Many brain-sparing, cerebroprotective, and/or infarct-limiting interventions have been

proposed in recent years, many based on the postulated mechanisms of asphyxial damage.
Administration of high-dose barbiturates to decrease cerebral metabolism and naloxone for
endogenous opioid blockade has proved ineffective in humans despite their initial promise
in animal models. Newer possibilities such as
(a) antagonists of excitotoxic neurotransmitter receptors (e.g., NMDA receptor blockers),
(b) free radical scavengers, antioxidants and xanthine oxidase inhibitors of (e.g.,
superoxide dismutase, catalase, vitamin E, dimethylthiourea , allopurinol,);
(c) Ca2+ channel blockers (e.g., nifedipine, nicardipine);
(d) cyclooxygenase inhibitors (e.g., indomethacin);
(e) hypothermia;
(f) benzodiazepine receptor stimulation (e.g., midazolam);
(g) enhancers of protein synthesis (e.g., dexamethasone);
(h) vasodilators (e.g., prostacyclin)
all have a theoretical basis, but have not yet undergone any systemic human trials and are
still experimental NONE USED IN PRACTICE

C. Effective CPR when indicated is the only therapy that has been
unequivocally shown to improve outcome in HIE.
M. Johnston/S.Donn
PCNA 20:2 June 93, pg. 463-
483
XV. Long term outcomes
 21

Clinical manifestations of neurologic sequelae. The precise neurologic sequelae one

will see following a severe asphyxic insult will reflect the location, identity, and extent of the
neural cellular population affected. CP is a nonprogressive motor and/or postural deficit of early
onset. The specific types—pyramidal, i.e., spastic quadriplegia commonly associated with
mental retardation and epilepsy; spastic diplegia (more commons in "preemies") or
hemiplegia; and extrapyramidal (including dystonic and choreoathetoid types)—are
determined by the topography of brain injury. Mixed varieties exist. Focal or multifocal cortical
necrosis, especially in the distribution of the middle cerebral artery, usually at the depths of
suici, may lead to pyramidal CP (unilateral or bilateral spastic hemiplegia or quadriplegia),
focal seizures, and mental retardation, depending on the extent of the damage. A boundary
zone infarct in a term newborn involving predominantly the parasagittal cortical regions (a
watershed between the anterior, middle, and posterior cerebral arteries) may be recognized as
weakness of the shoulder girdle and proximal upper extremities. Auditory, visual-spatial, or
language difficulties probably reflect more extensive parasagittal injury more laterally and
posteriorly in the border zones of the parietooccipital lobe. In the initially preterm infant, spastic
diplegia probably represents an ischemic cystic lesion in watershed zones of the periventricular
white matter at the angles of the ventricle superior to the germinal matrix (PVL); concomitant
visual Impairment suggests involvement of the optic radiations as well. Extrapyramldal CP is
probably the long-term clinical correlate of necrosis of the basal ganglia and thalamus (status
marmoratus).
PVL has been in 30-60% of asphyxiated term infants with spastic CP.
PVL in preterms usually results in, visual problems related to damage
to optic radiations,
loss of acuity, decreased visual field size, abnormal occular movements and
even blindness. HIE → brain stem injury → Cranial nerve nuclei III, IV & VI →
gaze abnormalities.
PVL in preterms often causes strabismus at 1 year of age.
Hearing loss 5-10% high frequency, sensori- neural loss in preterms –
baseline increased to 20% with HIE – 75% which were severe & 25%
profound.

Mechanism of damage may include: Cortical change

Hemorrhage in inner ear
Damage to auditory pathway within
brainstem
Damage to cochlear nuclei

Clin. Perin., 26:3, Sept. 1999, pgs. 766-78)

An appropriate specialists should follow up the infants with moderate or

severe HIE. Specialized rehabilitation systems are available in many
countries to counteract CP development. But this issue is out of scope of the
topic. Important to remember that too little could be done when cerebral
damage has occurred.

Summary:

• NO single tool or test can define perinatal asphyxia.

• Always incoporate antepartum, intrapartum and post partum
parameters.
 22

• ACOG and AAP, Committee on Maternal Fetal Medicine, Fetus and

the Newborn defined …

ESSENTIAL CHARACTERISTICS OF PERINATAL ASPHYXIA… as

A. Profound metabolic or mixed acidemia (pH <7.00) on an umbilical

cord arterial blood sample.
B. Persistence of an Apgar score of 0 to 3 for more than 5 minutes.
C. Clinical neurologic sequelae in the immediate neonatal period to
include seizures, hypotonia, coma, or HIE.
C. Evidence of multiorgan system dysfunction in the immediate
neonatal period.

**When they are lacking we cannot conclude that perinatal

asphyxia exists.

3.3. Suggested readings

1. Nelson textbook of pediatrics / Ed. by R.E.Behrman, R.M.Kliegman, W.E.Nelson,

V.C.Vaughan, III. – 15th ed. – Philadelphia etc.: W.B. Saunders Co, 1997. – P.458-459.
2. Hill A., Volpe J. Neurological disorders // Neonatology: pathophysiology and management
of the newborn / Ed. by G.B.Avery, M.A.Fletcher, M.G.MacDonald. – 4th edition. –
Philadelphia etc.: Lippincott Co, 1994. – P. 1121-1127.
3. Snyder E.Y., Cloherty J.P. Perinatal asphyxia // Manual of Neonatal Care / Ed. by J.P.
Cloherty, A.R.Stark. – 4th edition. – Philadelphia etc.: Lippincott-Raven, 1997. – P. 515-532.