27C
Perinatal Asphyxia
Lisa M. Adcock
Lu-Ann Papile
I. PERINATAL ASPHYXIA
refers to a condition of impaired gas exchange that leads, if persistent, to fetal
hypoxemia and hypercarbia. It occurs during the first and second stage of labor and is
identified by fetal acidosis, as measured in umbilical arterial blood. The umbilical artery
pH that defines asphyxia of a sufficient degree to cause brain injury is unknown.
Although the most widely accepted definition is a pH <7.0, even with this degree of
acidosis the likelihood of brain injury is low. The following terms may be used in
evaluating a term infant at risk for brain injury in the perinatal period:
A. Neonatal depression
is a general term used to describe an infant who has a prolonged transition from an
intrauterine to an extrauterine environment. These infants usually have low 1- and 5minute Apgar scores.
B. Neonatal encephalopathy
is a clinical term used to describe an abnormal neurobehavioral state that consists of a
decreased level of consciousness with abnormalities in neuromotor tone. It
characteristically begins within the first postnatal day and may be associated with
seizure-like activity, hypoventilation or apnea, depressed primitive reflexes and the
appearance of brain stem reflexes. It does not imply a specific etiology, nor does it
imply irreversible neurologic injury.
C. Hypoxic-ischemic encephalopathy (HIE)
is an abnormal neurobehavioral state in which the predominant pathogenic mechanism
is impaired cerebral blood flow.
D. Hypoxic-ischemic brain injury
refers to neuropathology attributable to hypoxia and/or ischemia as evidenced by
biochemical (such as serum creatine kinase brain bound [CK-BB]), electrophysiologic
(EEG), neuroimaging (head ultrasonography [HUS], magnetic resonance imaging
[MRI], computed tomography [CT]), or postmortem abnormalities.
II. INCIDENCE.
The frequency of perinatal asphyxia is approximately 1% to 1.5% of live births in the
Western Hemisphere and is inversely related to gestational age and birth weight. It
occurs in 0.5% of live born infants >36 weeks' gestation and accounts for 20% of
perinatal deaths (50% if stillborns are included). A higher incidence is noted in term
infants of diabetic or toxemic mothers, infants with intrauterine growth restriction,
breech presentation, and postdates infants.
III. ETIOLOGY.
In term infants, 90% of asphyxial events occur in the antepartum or intrapartum period
as a result of impaired gas exchange across the placenta that leads to the inadequate
provision of oxygen (O2) and removal carbon dioxide (CO2) and H+ from the fetus. The
remainder of these events occurs in the postpartum period and is usually secondary to
pulmonary, cardiovascular, or neurologic abnormalities.
A.
Factors that increase the risk of perinatal asphyxia include the following:
1. Impairment of maternal oxygenation.
2. Decreased blood flow from mother to placenta.
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3. Decreased blood flow from placenta to fetus.
4. Impaired gas exchange across the placenta or at the fetal tissue level.
5. Increased fetal O2 requirement.
B.
Etiologies of perinatal hypoxia-ischemia include the following:
1. Maternal factors: hypertension (acute or chronic), infection, diabetes, hypotension,
vascular disease, drug use, and hypoxia due to pulmonary, cardiac, or neurologic
disease.
2. Placental factors: infarction, fibrosis, abruption, or hydrops.
3. Uterine rupture.
4. Umbilical cord accidents: prolapse, entanglement, true knot, compression.
5. Abnormalities of umbilical vessels.
6. Fetal factors: anemia, infection, cardiomyopathy, hydrops, severe cardiac/ circulatory
insufficiency.
7. Neonatal factors: severe neonatal hypoxia due to cyanotic congenital heart disease,
persistent pulmonary hypertension of the newborn (PPHN), cardiomyopathy, other
forms of neonatal cardiogenic and/or septic shock.
IV. PATHOPHYSIOLOGY
A.
Events that occur during the normal course of labor cause most babies to be born with
little O2 reserve. These include the following:
1. Decreased blood flow to placenta due to uterine contractions, some degree of cord
compression, maternal dehydration, maternal alkalosis due to hyperventilation.
2. Decreased O2 delivery to the fetus as a result of the reduction of placental blood flow.
3. Increased O2 consumption in both mother and fetus.
B.
During labor complicated by a hypoxic-ischemic challenge, the following changes may
occur:
1. With brief asphyxia, there is a transient increase, followed by a decrease in heart rate
(HR), mild elevation in blood pressure (BP), an increase in central venous pressure
(CVP), and essentially no change in cardiac output (CO). This is accompanied by a
redistribution of CO with an increased proportion going to the brain, heart and adrenal
glands (diving reflex).
2. With prolonged asphyxia cerebral blood flow becomes dependent on systemic BP
(loss of cerebral vascular autoregulation). A decrease in CO leads to hypotension and
impaired cerebral blood flow resulting in anaerobic metabolism and eventual
intracellular energy failure due to an increase in the utilization of glucose in the brain
and a fall in the concentration of glycogen, phosphocreatine, and adenosine triphosphate
(ATP).
3. Hypoxia-induced vascular dilatation increases glucose availability, at least
transiently; and anaerobic metabolism produces lactic acid.
C.
Cellular changes occur due to diminished oxidative phosphorylation and ATP
production. This energy failure impairs ion pump function, causing accumulation of
intracellular Na+, Cl-, H2O, and Ca2+; extracellular K+; and excitatory amino acid (EAA)
neurotransmitters (e.g., glutamate). Impairment of oxidative phosphorylation can occur
during the primary asphyxial episode as well as during a secondary energy failure that
usually occurs approximately 6 to 24 hours after the initiating insult. Cell death can be
either immediate or delayed, and either apoptotic or necrotic.
1. Immediate neuronal death can occur due to intracellular osmotic overload of Na+ and
Ca2+, as seen with excessive EAA acting on inotropic glutamate receptors (such as the
N-methyl-D-aspartate [NMDA) receptor])
2. Delayed neuronal death occurs secondary to uncontrolled activation of enzymes and
second messenger systems within the cell (e.g., Ca2+-dependent lipases, proteases, and
caspases); perturbation of mitochondrial respiratory electron chain transport; generation
of free radicals and leukotrienes; generation of nitric oxide (NO) through NO synthase;
or depletion of energy stores.
3. EAA also can activate α-3-hydroxy-5-methyl-isoxazole (AMPA) receptor channels,
leading to oligodendrocyte progenitor cell death.
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4. Reperfusion of previously ischemic tissue may cause injury as it can promote the
formation of excess reactive oxygen species (e.g., superoxide, hydrogen peroxide,
hydroxyl, singlet oxygen), which can overwhelm the endogenous scavenger
mechanisms, thereby causing damage to cellular lipids, proteins, and nucleic acids, as
well as to the blood-brain barrier. This may result in an influx of neutrophils that, along
with activated microglia, release injurious cytokines (e.g., interleukin 1-β [IL-1 β] and
tumor necrosis factor α [TNF-α]).
V. DIAGNOSIS
A. Perinatal assessment of risk
includes awareness of preexisting maternal or fetal problems that may predispose to
perinatal asphyxia (see preceding list) and of changing placental and fetal conditions
(see Chap. 1) ascertained by ultrasonographic examination, biophysical profile,
nonstress tests, measurement of urinary estriol.
B. Clinical presentation
can be variable. Common clinical scenarios include a postdates infant with asphyxia,
meconium aspiration, pulmonary hypertension, pneumothorax, or birth trauma.
C. Low Apgar scores
and need for resuscitation in the delivery room are common but nonspecific findings.
Many features of the Apgar score relate to cardiovascular integrity and not neurologic
function.
1. In addition to perinatal asphyxia, the differential diagnosis for a term infant with an
Apgar score ≤3 for >5 minutes includes depression from maternal anesthesia or
analgesia; trauma; metabolic or infectious insults; neuromuscular disorders; and central
nervous system (CNS), cardiac, or pulmonary malformations
2. If the Apgar score is >6 by 5 minutes, perinatal asphyxia is not likely.
D.
Umbilical cord or first blood gas determination.
The specific blood gas criteria that define asphyxia causing brain damage are uncertain.
1. In a population-based cohort of 17,000 term infants, the average umbilical cord
arterial pH was 7.24 ± 0.07 and BE was -5.6 ± 0.3 mmol/L. Umbilical arterial pH <7.0
was present in only 0.4%. Of these, 5-minute Apgar score was <7 in 31% and <3 in
8.5%. The risk of adverse outcome was more likely if the acidosis is purely metabolic or
mixed.
2. In another study, base deficit was measured in term infants who had persistent
hemodynamic, respiratory, or neurologic abnormalities at 30 minutes of age. Metabolic
acidosis with base deficit of 14 mmol/L or more had a sensitivity of 73.2% and a
specificity of 82% in predicting moderate or severe neonatal encephalopathy. In two
large randomized clinical trials of hypothermia for neonatal hypoxic/ischemic
encephalopathy, severe acidosis was defined as pH of 7.0 or less or base deficit of ≥16
mmol/L.
VI. HIE.
The diagnosis of perinatal HIE requires an abnormal neurologic examination on the first
day following birth. It is important to note that no significant neurologic abnormality
diagnosed later in childhood (e.g., cerebral palsy [CP]) can be ascribed to perinatal
asphyxia in the absence of evidence in the immediate neonatal period of neurologic
abnormality and severe multiorgan dysfunction.
A.
The clinical spectrum of HIE is described as mild, moderate and severe (see Table
27C.1 Sarnat Stages of HIE). Infants can progress from mild to moderate and/or severe
encephalopathy over the 72 hours following the hypoxic-ischemic insult.
B.
The diagnosis of neonatal encephalopathy includes a number of etiologies in addition to
perinatal hypoxia-ischemia. Asphyxia may be suspected and HIE reasonably included in
the differential diagnosis of term neonatal depression, coma, or neurologic dysfunction
if the following have been documented:
1. Apgar score ≤3 at >5 minutes.
2. Fetal HR <60 beats/minute.
3. Prolonged (>1 hour) antenatal acidosis.
4. Seizures within first 24 to 48 hours after birth (50% of seizures are not asphyxial in
etiology).
5. Burst-suppression pattern electroencephalography (EEG).
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TABLE 27C.1 Sarnat and Sarnat Stages of Hypoxic-Ischemic Encephalopathy*
Stage
Stage 1
(Mild)
Stage 2 (Moderate)
Stage 3 (Severe)
Level of consciousness
Hyperalert;
irritable
Lethargic or obtunded
Stuporous,
comatose
Neuromuscular control: Uninhibited, Diminished spontaneous
overreactive movement
Diminished or
absent spontaneous
movement
Muscle tone
Normal
Mild hypotonia
Flaccid
Posture
Mild distal
flexion
Strong distal flexion
Intermittent
decerebration
Stretch reflexes
Overactive
Overactive, disinhibited
Decreased or
absent
Segmental myoclonus
Present or
absent
Present
Absent
Complex reflexes:
Normal
Suppressed
Absent
Suck
Weak
Weak or absent
Absent
Moro
Strong, low
threshold
Weak, incomplete high
threshold
Absent
Oculovestibular
Normal
Overactive
Weak or absent
Tonic neck
Slight
Strong
Absent
Autonomic function:
Generalized
sympathetic
Generalized
parasympathetic
Both systems
depressed
Pupils
Mydriasis
Miosis
Midposition, often
unequal; poor light
reflex
Respirations
Spontaneous Spontaneous; occasional
apnea
Periodic; apnea
Heart rate
Tachycardia Bradycardia
Variable
Bronchial and salivary
secretions
Sparse
Profuse
Variable
Gastrointestinal motility Normal or
decreased
Increased diarrhea
Variable
Seizures
Common focal or
Uncommon
multifocal (6 to 24 hours of (excluding
age)
decerebration)
None
Electroencephalographic Normal
findings
(awake)
Early: generalized lowEarly: periodic
voltage, slowing
pattern with
(continuous delta and theta)isopotential phases
Later: periodic pattern
Later: totally
(awake); seizures focal or isopotential
multifocal; 1.0 to 1.5 Hz
spike and wave
Duration of symptoms
<24 hours
2 to 14 days
Hours to weeks
Outcome
About 100% 80% normal; abnormal if About 50% die;
normal
symptoms more than 5 to 7 remainder with
days
severe sequelae
*
The stages in this table are a continuum reflecting the spectrum of clinical states of
infants over 36 weeks' gestational age.
Source: From Sarnat H. B., Sarnat M. S. Neonatal encephalopathy following fetal
distress: A clinical and electroencephalographics study. Arch Neurol 1976;33:696.
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6. Need for positive pressure ventilation for >1 minute or first cry delayed >5 minutes.
VII. OTHER NEUROLOGIC CONSIDERATIONS
A. Increased intracranial pressure (ICP),
defined as >10 mm Hg, or cerebral edema should be regarded as an effect rather than a
cause of brain damage. Cerebral edema peaks at 36 to 72 hrs after the insult. It often
reflects extensive prior cerebral necrosis rather than swelling of intact cells, making this
finding consistent with a uniformly poor prognosis. Efforts to reduce ICP and cerebral
edema (high-dose phenobarbital, steroids, mannitol, and other hypertonic solutions) do
not affect outcome.
B. Seizures
are described in 20% to 50% of infants with HIE, and usually start between 6 and 24
hours after the insult. They are most often seen in Sarnat stage 2 HIE, rarely in Sarnat
stage 3, and almost never in Sarnat stage 1 HIE.
1. Seizures in HIE are usually subtle, tonic, or multifocal clonic. Generalized seizures
are uncommon due to comparatively immature myelinization and synaptogenesis of the
neonatal brain. Distinguishing between multifocal seizures and jitteriness (rhythmic
segmental myoclonus) in stages 1 and 2 HIE may be difficult. They can be
differentiated by holding the affected extremity and changing the tension on the muscle
stretch receptor by slightly flexing or extending the joint. This should arrest clonus,
whereas in true seizures, convulsive movements continue to be felt in the examiner's
hand.
2. Seizures may be associated with increased cerebral metabolic rate, which could lead
to further cerebral injury.
3. Seizures can compromise ventilation and oxygenation, especially in infants who are
not on mechanical ventilation. In infants on musculoskeletal blockade for mechanical
ventilation, seizures may be manifested by abrupt changes in BP, HR and oxygenation.
4. Seizures associated with HIE are often very difficult to control. Whether seizures
alone, in the absence of metabolic or cardiopulmonary abnormalities, lead to brain
injury is controversial.
VIII. MULTIORGAN DYSFUNCTION.
Other organ systems in addition to the brain usually exhibit evidence of asphyxial
damage.
A.
In some cases, the brain may be the only organ exhibiting dysfunction following
asphyxia. In one series of 57 infants, HIE occurred without other system involvement in
14 (24.5%).
B.
The gamut of organ involvement in perinatal asphyxia varies among series, depending
in part upon the definitions used for asphyxia and organ dysfunction.
1. In a retrospective study of 130 term infants with asphyxia, the proportion of those
with organ dysfunction was: renal 70%, cardiovascular 62%, pulmonary 86%, hepatic
85%. Infants were diagnosed with asphyxia if they needed mechanical ventilation at
birth, exhibited encephalopathy, and had one or more of the following: (i) 5-minute
Apgar score <5, (ii) Base deficit 16 or more mmol/L documented within first hour of
life, and (iii) delayed respiratory effort for 5 or more minutes of life.
2. In another series of 152 asphyxiated term infants followed prospectively, neurologic
and systemic complications occurred in 43% and 57%, respectively. Organ dysfunction
included respiratory abnormalities 39%, infection 17%, gastrointestinal intolerance
15%. Infants were considered to have asphyxia if they had fetal distress, were depressed
at birth, and exhibited a metabolic acidosis.
C.
Multiorgan dysfunction is theorized to be secondary to the “diving reflex” (see IV B 1).
1. The kidney is the most common organ to be affected in perinatal asphyxia. The
proximal tubule of the kidney is especially affected by decreased perfusion, leading to
acute tubular necrosis (ATN) (see Chap. 31).
2. Cardiac dysfunction is caused by transient myocardial ischemia. The ECG may show
ST depression in the midprecordium and T-wave inversion in the left precordium.
Echocardiographic findings include decreased left ventricular
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contractility, especially of posterior wall; elevated ventricular end-diastolic pressures;
tricuspid insufficiency and pulmonary hypertension due to poor ventricular function. In
severely asphyxiated infants, dysfunction more commonly affects the right ventricle. A
fixed HR may raise suspicion of clinical brain death.
3. Gastrointestinal effects include an increased risk of bowel ischemia and necrotizing
enterocolitis (see Chap. 32).
4. Hematologic effects include disseminated intravascular coagulation due to damage to
blood vessels, poor production of clotting factors due to liver dysfunction, and poor
production of platelets by the bone marrow.
5. Liver involvement may be manifested by isolated elevation of hepatocellular
enzymes. More extensive damage may occur, leading to DIC, inadequate glycogen
stores with resultant hypoglycemia, or altered detoxification or elimination of drugs.
6. Pulmonary effects include increased pulmonary vascular resistance leading to PPHN,
pulmonary hemorrhage, pulmonary edema due to cardiac dysfunction, secondary RDS
due to failure of surfactant production, and meconium aspiration.
IX. LABORATORY EVALUATION OF EFFECTS OF ASPHYXIA
A. Cardiac evaluation
1. Cardiac troponin I (cTNI) and cardiac troponin T (cTnT), cardiac regulatory proteins
that control the calcium-mediated interaction of actin and myosin, are markers of
myocardial damage. Normal values in the neonate are troponin I = 0 - 0.28 ± 0.42 µg/L
and troponin T = 0 - 0.097 µg/L. Elevated levels of these proteins have been described
in infants with clinical and laboratory evidence of asphyxia.
2. An elevation of serum creatine kinase myocardial bound (CK-MB) fraction of >5%
to 10% may indicate myocardial injury.
B.
Brain injury.
1. Serum CK-BB. This may be increased in asphyxiated infants within 12 hours of the
insult, but has not been correlated with long-term neurodevelopmental outcome. CK-BB
is also expressed in placenta, lungs, gastrointestinal tract, and kidneys.
2. In one report, measurement of protein S-100 (>8.5 µg/L) plus elevated CK-BB, or
elevated CK-BB and low cord blood arterial pH had sensitivity of 71% each and
specificity of 95% and 91% respectively in predicting moderate to severe
encephalopathy.
C. Renal evaluation
1. Blood urea nitrogen (BUN) and serum creatinine (Cr) may be elevated in perinatal
asphyxia. Typically elevation is noted 2 to 4 days after the insult.
2. Fractional excretion (FE) of Na+ or renal failure index may help confirm renal insult
(see Chap. 31).
3. Urine levels of β-2-microglobulin have been used as an indicator of proximal tubular
dysfunction, although not routinely. This low molecular weight protein is freely filtered
through the glomerulus and reabsorbed almost completely in the proximal tubule.
4. Renal sonographic abnormalities correlate with the occurrence of oliguria.
X. CRANIAL IMAGING
A. Cranial sonographic
examination is less useful than other imaging modalities in assessing edema, subtle
midline shift, superficial cortical or posterior fossa hemorrhage, and ventricular
compression.
B. Computed tomography (CT)
may be useful for determining the extent of cerebral edema, especially when performed
2 to 4 days after the insult.
C. Magnetic resonance imaging (MRI).
T1- and T2-weighted MRI has been considered the best modality for imaging the
neonatal brain; however, standard MRI may not detect hyoxic-ischemic changes during
the first few days after the insult. High signal on T2-weighted images represents
vasogenic edema.
1. Diffusion-weighted images (DWI) can show abnormalities within hours of the insult
that may yield prognostic information. By detecting differences in rates
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of diffusion of water protons, DWI reveals restricted water diffusion, reflecting
cytotoxic edema that is not apparent on conventional MRI. However, DWI does not
distinguish cytotoxic edema from cell death, especially in global diffuse injuries, during
the first hours following a hypoxic-ischemic insult.
2. Localized magnetic resonance spectroscopy (MRS), also called proton-MRS or 1HMRS, measures the relative concentrations of various metabolites in tissue. Elevated
lactate and abnormal ratios of choline to total creatine and N-acetylaspartate (NAA) to
total creatine have been described following neonatal hypoxic-ischemic brain injury and
may yield prognostic information.
XI. EEG
is used both to evaluate for seizure activity and also to define abnormal background
activity such as burst-suppression, continuous low voltage, or isoelectric patterns. When
expertise in interpretation of neonatal EEGs is not readily available, amplitude
integrated EEG (aEEG) has been used to evaluate for seizures and to define abnormal
background patterns. This method consists of a single-channel EEG from biparietal
electrodes. There is selective filtering of specific channels (<2 Hz and >15 Hz), then
integration of the signal amplitude and semilogarithmic recording of the processed
signal.
XII. PATHOLOGIC FINDINGS OF BRAIN INJURY
A.
Specific neuropathology may be seen after moderate or severe asphyxia.
1. Focal or multifocal cortical necrosis affecting all cellular elements can result in cystic
encephalomalacia and/or ulegyria (attenuation of depths of sulci) due to loss of
perfusion in one or several vascular beds.
2. Watershed infarcts occur in boundary zones between cerebral arteries, particularly
following severe hypotension. They reflect poor perfusion of the vulnerable
periventricular border zones in the centrum semiovale and produce predominantly white
matter injury. In the term infant, this typically results in bilateral parasagittal cortical
and subcortical white matter injury or injury to the parieto-occipital cortex.
3. Selective neuronal necrosis is the most common type of injury seen following
perinatal asphyxia. It is due to differential vulnerability of specific cell types; for
example, neurons are more easily injured than glia. Specific regions at increased risk are
CA1 region of hippocampus, Purkinje cells of cerebellum in term infants, and brainstem
nuclei. Necrosis of thalamic nuclei and basal ganglia (status marmoratus) can be
considered a subtype of selective neuronal necrosis.
B.
Neuropathology may reflect the type of asphyxial episode, although the precise pattern
is not predictable.
1. Prolonged partial episodes of asphyxia tend to cause diffuse cerebral (especially
cortical) necrosis. Expected clinical findings usually include seizures and paresis.
2. Acute total asphyxia tends to spare the cortex although affecting primarily the
brainstem, thalamus, and basal ganglia. Expected clinical findings usually include
disturbances in consciousness, respiration, HR, BP, and temperature control; disorders
of tone and reflexes; cranial nerve palsies.
3. Partial prolonged asphyxia followed by a terminal acute asphyxial event
(combination) is probably present in most cases.
XIII. TREATMENT
A. Perinatal management of high-risk pregnancies
1. Fetal HR and rhythm abnormalities may provide supporting evidence of asphyxia,
especially if accompanied by presence of thick meconium. However, they provide no
information concerning duration or severity of an asphyxial event.
2. Measurement of fetal scalp pH is a better determinant of fetal oxygenation than Po2.
With intermittent hypoxia-ischemia, Po2 may improve transiently whereas the pH
progressively falls. Fetal scalp blood lactate has been suggested as easier and more
reliable than pH, but has not gained wide acceptance.
3. Close monitoring of progress of labor with awareness of other signs of in utero stress.
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4. The presence of a constellation of abnormal findings may indicate the need to
mobilize the perinatal team for a newborn that could require immediate intervention.
Alteration of delivery plans may be indicated and guidelines for intervention in cases of
suspected fetal distress should be designed and in place in each medical center (see
Chap. 1).
B. Delivery room management
(see Chaps. 4, 17, and 24).
The initial management of the hypoxic-ischemic infant in the delivery room is described
in Chapter 4.
C. Postnatal management of neurologic effects of asphyxia
1. Ventilation. CO2 should be maintained in the normal range. Hypercapnia can cause
cerebral acidosis and cerebral vasodilation. This may result in more flow to uninjured
areas and relative ischemia to damaged areas (“steal phenomenon”). Excessive
hypocapnia (CO2 <25 mm Hg) may decrease CBF.
2. Oxygenation. Oxygen levels should be maintained in the normal range, although poor
peripheral perfusion may limit the accuracy of continuous noninvasive monitoring.
Hypoxemia should be treated with supplemental O2 and/or ventilation. Hyperoxia may
cause decreased CBF or exacerbate free radical damage.
3. Temperature should be maintained in the normal range and hyperthermia should be
avoided.
4. Perfusion. Cardiovascular stability and adequate mean systemic arterial BP are
important in order to maintain adequate cerebral perfusion pressure.
5. Maintain physiologic metabolic state
a. Hypocalcemia is a common metabolic alteration after neonatal asphyxia. It is
important to maintain calcium in the normal range, because hypocalcemia can
compromise cardiac contractility and may cause seizures (see Chap. 29B,
Hypocalcemia, Hypercalcemia, and Hypermagnesemia Glucose); (see Chaps. 27A).
b. Hypoglycemia is often seen in asphyxiated infants.
Blood glucose level should be maintained in the normal range for term infants.
Hyperglycemia may lead to an increase in brain lactate, damage to cellular integrity,
increased edema, or further disturbance in vascular autoregulation. Hypoglycemia may
potentiate excitotoxic amino acids.
6. Judicious fluid management is needed and fluid overload should be avoided. Two
processes predispose to fluid overload in asphyxiated infants:
a. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (see Chap. 9)
is often seen 3 to 4 days after the hypoxic-ischemic event. It is manifested by
hyponatremia and hypo-osmolarity in combination with inappropriately concentrated
urine (elevated urine specific gravity, osmolarity, and Na+).
b. ATN (see Chap. 31) can result from the “diving reflex” (see preceding text).
c. Fluid restriction may aid in minimizing cerebral edema although the effect of fluid
restriction on long-term outcome in infants who are not in renal failure is not known.
7. Control of seizures. Seizures secondary to asphyxia are generally self-limited to the
first few postnatal days. Because they are extremely difficult to control, it may not be
possible to eliminate them completely. Once levels of conventional anticonvulsants are
maximized, there is little utility in eliminating every “twitch” or electrographic seizure
unless there is cardiopulmonary compromise from the seizures. In infants on
musculoskeletal blockade, seizures may be manifested by abrupt changes in BP, HR,
and oxygenation. Whether seizures, per se, cause brain injury is unknown. There is
inadequate evidence to support the continued use of anticonvulsants in the absence of
clinical or electrical (EEG) seizures. Metabolic perturbations such as hypoglycemia,
hypocalcemia, hyponatremia, should be excluded before initiating anticonvulsant
therapy.
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a. Acute use of anticonvulsants
i. Phenobarbital is the initial drug of choice. It is given as a loading dose of 20 mg/kg
IV. If seizures continue, an additional loading dose of 10 to 20 mg/kg IV may be given.
A maintenance dose of 3 to 5 mg/kg/day PO or IV divided BID should be started 12 to
24 hours after the loading dose. Intramuscular (IM) is avoided because absorption is too
slow. During initiation, the infant needs to be monitored closely for respiratory
depression. Therapeutic serum levels are 20 to 40 mg/dL. Because a prolonged serum
half-life due to renal compromise may result in drug accumulation, serum levels need to
be monitored closely and the maintenance dose adjusted accordingly.
ii. Phenytoin is usually added when seizures are not controlled by phenobarbital. The
loading dose is 15 to 20 mg/kg IV followed by a maintenance dose of 4 to 8 mg/kg/day.
In many centers, phosphenytoin is used in place of parent drug (phenytoin) because the
risk of hypotension is less and extravasation has no adverse effects. Dosage is
calculated and written in terms of phenytoin equivalents to avoid medication errors.
Therapeutic serum level is typically 20 mg/dL.
iii. Benzodiazapenes are considered third-line drugs and include lorazepam 0.05 to 0.1
mg/kg/dose IV.
b. Long-term anticonvulsant management. Anticonvulsant therapy can be weaned when
the clinical exam and EEG indicate that the infant is no longer having seizures. If the
infant is receiving more than one anticonvulsant, weaning should be in the reverse order
of initiation, with phenobarbital being weaned last. Phenobarbital is then tapered over
several weeks. If there is EEG evidence of seizure activity, phenobarbital should be
continued for 3 to 6 months. Approximately 25% of infants will need ongoing
anticonvulsant therapy. Infants who have a high risk of recurring seizures in infancy or
childhood are those with persistent neurologic deficit (50%) and those with an abnormal
EEG between seizures (40%)
8. Management of other target organ injury
a. Cardiac dysfunction should be managed with correction of hypoxemia, acidosis, and
hypoglycemia and avoidance of volume overload. Diuretics may not be helpful if
concomitant renal impairment is present. Infants will require continuous monitoring of
systemic mean arterial BP, CVP (if available), and urine output. Infants with
cardiovascular compromise may require inotropic drugs such as dopamine (see Chap.
17) and may need afterload reduction with a peripheral β-antagonist (e.g., isoproterenol)
or phosphodiesterase inhibitor (e.g., milrinone) to maintain BP and perfusion.
i. Arterial BP should be maintained in the normal range to support adequate cerebral
perfusion.
ii. Monitoring of CVP may be helpful to assess adequacy of preload (i.e., that the infant
is not hypovolemic due to vasodilatation or third spacing); a reasonable goal is 5 to 8
mm Hg in term infants.
b. Renal dysfunction should be monitored by measuring urine output, and with
urinalysis, urine specific gravity, paired urine/serum osmolarity and serum electrolytes.
i. In the presence of oliguria or anuria avoid fluid overload by limiting free water
administration to replacement of insensible losses and urine output (~60 mL/kg/day)
and consider using low-dose dopamine infusion (≤5 µg/kg/min) (see Chaps. 9 and 31).
ii. Volume status should be evaluated before instituting strict fluid restriction. If there is
no or low urine output, a 10 to 20 mL/kg fluid challenge followed by a loop diuretic
such as furosemide may be helpful.
iii. To avoid fluid overload, as well as hypoglycemia, concentrated glucose infusions
delivered through a central line may be needed. Glucose levels
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should be monitored closely and rapid glucose boluses avoided. Infusions should be
weaned slowly to avoid rebound hypoglycemia.
c. Gastrointestinal effects. Feeding should be withheld until good bowel sounds are
heard and stools are negative for blood and/or reducing substances (see Chap. 32).
d. Hematologic abnormalities (see Chap. 26). Coagulation profile is monitored with
partial thromboplastin time (PTT) and prothrombin time (PT), fibrinogen, and platelets.
Abnormalities may need to be corrected with fresh frozen plasma, cryoprecipitate,
and/or platelet infusions.
e. Liver function should be monitored with measurement of transaminases (ALT, AST),
clotting (PT, PTT, fibrinogen), albumin, bilirubin, and ammonia. Levels of drugs that
are metabolized or eliminated through the liver must be monitored.
f. Lung (see Chap. 24). Management of the pulmonary effects of asphyxia depends on
the specific condition.
XIV. NEUROPROTECTIVE STRATEGIES.
A number of neuroprotective strategies have been proposed.
A.
Agents tested in animals with little data in human newborns include antagonists of
excitotoxic neurotransmitter receptors such as NMDA receptor blockade with ketamine
or MK-801; free radical scavengers such as allopurinol, superoxide dismutase, and
vitamin E; Ca2+-channel blockers such as magnesium sulfate, nimodipine, nicardipine;
cyclooxygenase inhibitors such as indomethacin; benzodiazepine receptor stimulation
such as midazolam; and enhancers of protein synthesis such as dexamethasone.
B.
Mild induced hypothermia used under strict experimental protocols may be a potentially
useful treatment for acute perinatal asphyxia based on short-term outcomes (18 months)
in two randomized clinical trials. However, the results of ongoing trials and long-term
efficacy and safety need to be established before this therapeutic modality can be
considered standard of care.
XV. OUTCOME IN PERINATAL ASPHYXIA
A.
The overall mortality rate is 10% to 30%. The frequency of neurodevelopmental
sequelae in surviving infants is approximately 15% to 45%.
B.
The risk of CP in survivors of perinatal asphyxia is 5% to 10% compared to 0.2% in the
general population. Most CP is not related to perinatal asphyxia, and most perinatal
asphyxia does not cause CP. Only 3% to 13% of infants with CP have evidence of
intrapartum asphyxia.
C.
Specific outcomes depend on the severity of the encephalopathy, the presence or
absence of seizures, EEG results, and neuroimaging findings
1. Severity of encephalopathy can be ascertained using the Sarnat clinical stages of HIE
(Table 27C.1).
a. Stage 1 HIE: 98% to 100% of infants will have a normal neurologic outcome and <
1% mortality.
b. Stage 2 HIE: 20% to 37% die or have abnormal neurodevelopmental outcomes.
Infants who exhibit Stage 2 signs for >7 days have poorer outcomes. In one study, half
of the 42 surviving infants who had Sarnat stage 2 encephalopathy had normal
neurodevelopment at 1 year of age; approximately 10% had a normal neurologic exam
and mild developmental delay and one-third were diagnosed with CP.
c. Stage 3 HIE: 50% to 89% die and all survivors have major neurodevelopmental
impairment.
d. Prognosis is considered to be good if an infant does not progress to and/or remains in
stage 3 and if total duration of stage 2 is <5 days.
e. Some neurologically normal survivors of perinatal asphyxia have problems in school.
In one study, all stage 1 HIE and 65% to 82% of stage 2 HIE children performed at
expected grade level at 8 years. In another study, children 8 to 13 years' old who had
neonatal encephalopathy plus Apgar score <4 had increased risk of problems with
mathematics (3.3 times higher), problems with reading (4.6 times higher), epilepsy (7
times higher),
P.528
minor motor problems (13 times greater), attention deficit-hyperactivity disorder (14
times greater) compared to unaffected children.
2. The presence of seizures increases an infant's risk of CP 50 to 70 fold. Mortality risk
is highest for seizures that begin within 12 hours of birth (53%). In one study, infants
whose seizure duration was 1 day had a 7% rate of CP and 11% had epilepsy on followup. If seizures lasted for >3 days, the rates of CP and epilepsy were 46% and 40%
respectively.
3. The detection of low voltage activity, electrocerebral inactivity or burst-suppression
patterns on EEG is a better prognostic indicator of poor outcome than is the finding of
epileptiform activity. In particular, 93% of neonates with extreme burst suppression
activity have poor outcomes. Persistent burst suppression is associated with an 86% to
100% risk of death or severe neurodevelopmental sequelae.
4. Normal findings on DWI MRI between 2 and 18 days of age are associated with
normal neuromotor outcome at 12 to 18 months. Abnormalities of deep gray matter that
are detected early have the worse motor and cognitive outcomes. In one study, abnormal
DWI of the basal ganglia noted within 10 days of a hypoxic-ischemic insult was
associated with a 93% risk of abnormal neurodevelopmental outcome at 9 months to 5
years.
Suggested Readings
ACOG Task Force on Neonatal Encephalopathy and Cerebral Palsy. Neonatal
encephalopathy and cerebral palsy: Defining the pathogenesis and pathophysiology.
Washington, DC: American College of Obstetricians and Gynecologists, 2003.
Blackmon LR, Stark AR. Hypothermia: A neuroprotective therapy for neonatal
hypoxic-ischemic encephalopathy. Pediatrics 2006;117:942-948.
Edwards AD, Azzopardi DV. Therapeutic hypothermia following perinatal asphyxia.
Arch Dis Child Fetal Neonatal Ed 2006;91:F127-F131.
Higgins RD, Raju TNK, Perlman J, et al. Hypothermia and perinatal asphyxia:
Executive summary of the National Institute of Child Health and Human Development
Workshop. J Pediatr 2006;148:170-175.