Hypoxia - Ischemic Encephalopathy

Hypoxia - Ischemic Encephalopathy Ji ling

Background 

HIE is an acquired syndrome characterized by clinical and laboratory evidence of acute brain injury due to asphyxia (ie, hypoxia, acidosis).

Background 

In spite of major advances in monitoring technology and knowledge of fetal and neonatal pathologies, perinatal asphyxia or, more appropriately, hypoxic-ischemic encephalopathy (HIE), remains a serious condition, causing significant mortality and long-term morbidity.

Pathophysiology Brain hypoxia and ischemia from systemic hypoxemia and reduced cerebral blood flow (CBF) are the primary triggering events for HIE.  Cerebral autoregulation of CBF maintains brain perfusion (for awhile) in spite of an initial drop in the mean BP. 

Pathophysiology 

With prolonged asphyxia, the early compensatory adjustments fail; CBF may become "pressurepassive," at which time brain perfusion is dependent on systemic BP. As BP falls, CBF falls below critical levels and brain hypoxia occurs. This results in intracellular energy failure. During the early phases of brain injury, brain temperature drops and local release of the neurotransmitter GABA increases; these changes reduce cerebral oxygen demand, transiently minimizing the impact of asphyxia.

Pathophysiology Reperfusion injury is a second determinant of the extent of brain damage.  By 6-24 hours after the initial injury, a new phase of neuronal destruction sets in, characterized by apoptosis (ie, programmed cell death). Also known as "delayed injury," this phase may continue for days to weeks. 

Pathophysiology 

The severity of brain injury in this phase correlates well with the severity of longterm adverse neurodevelopmental outcome in infants. Modern treatment interventions are geared to reducing the neuronal destruction that occurs during this phase of HIE.

Pathophysiology A large cascade of biochemical events follow HIE injury.  Both hypoxia and ischemia increase the release of excitatory amino acids (EAAs [glutamate and aspartate]) in the cerebral cortex and basal ganglia. EAAs begin causing neuronal death immediately . 

Pathophysiology 



the destruction of ion pumps is the lipid peroxidation of cell membranes, in which enzyme systems, such as the Na+/K+-ATPase, reside. This leads to influx into the cell water, cell swelling, and death. EAAs also increase the local release of nitric oxide (NO), which may exacerbate neuronal damage, although its mechanisms are unclear.

Mortality/Morbidity In severe HIE, the mortality rate is as high as 50%. Half of the deaths occur in the first month of life. Some infants with severe neurologic disabilities die in infancy from aspiration pneumonia and other infections.  Among infants who survive severe HIE, the most frequent sequelae are mental retardation, epilepsy, and cerebral palsy 

Mortality/Morbidity The incidence of long-term complications depends on the severity of HIE.  Up to 80% of infants surviving severe HIE are known to develop serious complications, 10-20% develop moderately serious disabilities, and up to 10% are normal. 

Mortality/Morbidity Among the infants who survive moderately severe HIE, about 30-50% have serious long-term complications, and 10-20% have minor complications.  Infants with mild HIE tend to be free from serious CNS complications. 

Mortality/Morbidity 

Even in the absence of obvious neurologic deficits in the newborn period, there may be long-term functional impairments. Of school-aged children with a history of moderately severe HIE, 15-20% had significant learning difficulties, even in the absence of obvious signs of brain injury. Because of this, all children who have moderately severe or severe HIE as infants should be monitored well into their school-age years.

CLINICAL  a)

b) c)

History: Profound metabolic or mixed acidemia (pH <7.00) in an umbilical artery blood sample, if obtained Persistence of an Apgar score of 0-3 for longer than 5 minutes Neonatal neurologic sequelae (eg, seizures, coma, hypotonia)for more than 24h

Apgar score

It is a useful quantitative assessment of the infant’s condition and is commonly determined at 1 and 5 minutes after birth.

Apgar score evaluation of the newborn

criteria

score 0

1

2

Heart rate

absent

<100 beats/min

>100 beats/min

Respiratory effort Muscle tone

Absent/weak

Slow,irregular/gasping

Good,regular

Limp,flaccid

Some flexion

Active

weak

movements Cries,coughs

Reflex response to stimulation Colour of the body

none

sneezes Blue or pale

Extremities blue

pink

or

CLINICAL History: d) Multiple organ involvement (eg, of the kidney, lungs, liver, heart, intestines) e) On rare occasions, difficulties with delivery, particularly problems with delivering the "after-coming" head in breech presentation, suggest an alternate diagnosis of hemorrhage in the posterior cerebral fossa, which is a rare condition. 

CLINICAL   1) 2)

3)

Physical: Clinical manifestations and course vary depending on HIE severity. Mild HIE Muscle tone may be increased slightly and deep tendon reflexes may be brisk during the first few days. Transient behavioral abnormalities, such as poor feeding, irritability, or excessive crying or sleepiness, may be observed. By 3-4 days of life, the CNS examination findings become normal.

CLINICAL  1) 2) 3) 4) 5) 6)

Moderately severe HIE The infant is lethargic, with significant hypotonia and diminished deep tendon reflexes. The grasping, Moro, and sucking reflexes may be sluggish or absent. The infant may experience occasional periods of apnea. Seizures may occur within the first 24 hours of life. Full recovery within 1-2 weeks is possible and is associated with a better long-term outcome. An initial period of well-being may be followed by sudden deterioration, suggesting reperfusion injury; during this period, seizure intensity might increase.

CLINICAL  1) 2) 3) 4)

Severe HIE Stupor or coma is typical. The infant may not respond to any physical stimulus. Breathing may be irregular, and the infant often requires ventilatory support. Generalized hypotonia and depressed deep tendon reflexes are common. Neonatal reflexes (eg, sucking, swallowing, grasping, Moro) are absent.

CLINICAL 5)Disturbances

of ocular motion, such as a skewed deviation of the eyes, nystagmus, bobbing, and loss of "doll's eye" (ie, conjugate) movements may be revealed by cranial nerve examination. 6)Pupils may be dilated, fixed, or poorly reactive to light.

CLINICAL 7)Seizures occur early and often and may be initially

resistant to conventional treatments. The seizures are usually generalized, and their frequency may increase during the 2-3 days after onset, correlating with the phase of reperfusion injury. As the injury progresses, seizures subside and the EEG becomes isoelectric or shows a burst suppression pattern. At that time, wakefulness may deteriorate further, and the fontanelle may bulge, suggesting increasing cerebral edema.

CLINICAL 8)Irregularities

of heart rate and BP are common during the period of reperfusion injury, as is death from cardiorespiratory failure.

CLINICAL 

Involvement of multiple organs besides the brain is a hallmark of HIE.

1)

Severely depressed respiratory and cardiac functions and signs of brainstem compression suggest a life-threatening rupture of the vein of Galen (ie, great cerebral vein) with a hematoma in the posterior cranial fossa. Reduced myocardial contractility, severe hypotension, passive cardiac dilatation, and tricuspid regurgitation are noted frequently in severe HIE.

2)

CLINICAL Patients may have severe pulmonary hypertension requiring assisted ventilation. 4) Renal failure presents as oliguria and, during recovery, as high-output tubular failure, leading to significant water and electrolyte imbalances. 5) Intestinal injuries may not be apparent in the first few days of life. Poor peristalsis and delayed gastric emptying are common; necrotizing enterocolitis occurs rarely. 3)

•Table 1. Sarnat and Sarnat's 3 Clinical Stages of Hypoxic Ischemic Brain Injury

Level of Consciousness

State 1

Stage 2

Stage 3

Hyperalert

Lethargic or obtunded

Stuporous or coma

Neuromuscular Control Muscle tone

Normal

Mild hypotonia

Flaccid

Posture

Mild distal flexion

Strong distal flexion

Intermittent decerebration

Stretch reflexes

Overactive

Overactive

Decreased or absent

Segmental myoclonus

Present

Present

Absent

State 1

Stage 2

Stage 3

Complex Reflexes Suck

Weak

Weak or absent

Strong;

Weak; incomplete;

Oculovestib ular

Normal

Overactive

Weak or absent

Tonic neck

Slight

Strong

Absent

Moro

Autonomic Function

Generalized sympathetic

Absent Absent

Generalized parasympatheti c

Both systems depressed

Pupils

Mydriasis

Miosis

Variable; often unequal; poor light reflex

Heart Rate

Tachycardia

Bradycardia

Variable

Bronchial and Salivary Secretions

Sparse

Profuse

Variable

State 1 Gastrointestin al Motility

Seizures

Stage 2

Stage 3

Normal or decreased

Increased; diarrhea

Variable

None

Common; focal or multifocal

Uncommon (excluding decerebration)

Electroenceph alogram Findings

Normal (awake )

Early: low-voltage continuous delta and theta Later: periodic pattern (awake) Seizures: focal 1-to 1-Hz spike-and-wave

Early: periodic pattern with Isopotential phases Later: totally isopotential

Duration

<24 h

2-14

Hours to weeks

DIFFERENTIALS Other Problems to be Considered:  Brain tumors Developmental defects Infections Inherited metabolic disorders such as disorders of urea cyclase deficiency

workup

Lab Studies: No specific test excludes or confirms a diagnosis of HIE. Serum electrolytes, Renal function studies  Imaging Studies: Cranial ultrasound CT scan of the head MRI  Other Tests: EEG 

Treatment Medical Care:  Treatment of seizures is an essential component of management. Seizures should be treated with phenobarbital or lorazepam; 

Treatment 

Drug Category: Anticonvulsants -- Used to control seizures Phenobarbital 20 mg/kg IV over 10-15 min as loading dose; additional 5-10 mg/kg IV as loading dose; followed by 3-5 mg/kg/d

Treatment Cardiovascular (inotropic) agents -Increase BP and combat shock. Dopamine (Intropin) 2-20 mcg/kg/min IV continuous infusion; begin at lower doses, increase on basis of systemic BP appropriate for age and gestational age



Treatment 

No specific therapy for HIE exists; after seizure control, supportive care remains the cornerstone of management. The elements of supportive care are as follows:

Treatment •

•

Maintain adequate ventilation, perfusion, and metabolic status; most infants with HIE need ventilatory support during the first week. Prevent hypoxia, hypercapnia, and hypocapnia; the latter is due to inadvertent hyperventilation, which may lead to severe hypoperfusion of the brain.

Treatment •

•

•

Maintain the blood gases and acid-base status in the physiological ranges including partial pressure of arterial oxygen (PaO2), 80-100 mm Hg; partial pressure of arterial carbon dioxide (PaCO2), 35-40 mm Hg; and pH, 7.35-7.45. Maintain the mean BP above 35 mm Hg (for term infants). Dopamine or dobutamine can be used to maintain adequate cardiac output. Fluid, electrolyte, and nutritional status should be monitored and corrected and adequate calories and proteins provided.

Treatment o o

o

Avoid hypoglycemia or hyperglycemia, as both are known to cause brain injury. In the first 2 days of life, restrict intravenous fluids to two thirds of the daily requirement for gestational age and nursing environment in light of the high frequency of acute tubular necrosis and IADH. Individualize fluid and electrolyte therapy on the basis of clinical course, changes in weight, urine output, and results of serum electrolyte and renal function studies.

Prevention 

Most of the treatments discussed here are experimental. With the exception of hypothermia, which is still being examined in clinical trials, none of the therapies cited below has been consistently shown to have efficacy in human infants.

Prevention •

•

Allopurinol: Slight improvements in survival and CBF were noted in a small group of infants tested with this free-radical scavenger in one clinical trial. High-dose phenobarbital: In another study, 40 mg/kg phenobarbital was given over 1 hour to infants with severe HIE.

Prevention •

EAA antagonists: MK-801, an EAA antagonist, has shown promising results in experimental animals . This drug has serious cardiovascular adverse effects.

Prevention 

Hypothermia: Currently being intensely tested as a neuroprotective therapy, hypothermia's mechanism of protection is not completely understood. Explanations include (1) reduced metabolic rate and energy depletion; (2) decreased excitatory transmitter release; (3) reduced alterations in ion flux; and (4) reduced vascular permeability, edema, and disruptions of blood-brain barrier functions. The current state-of-the-art on hypothermia is summarized by the following:

Cooling Insult

Latent EEG low CBF↓ Apoptotic cascade

Secdonary Seizure Cytotoxic edema

Excitoxin

Reperfusion

Min,~30

H, 6~15

D, 3

Prevention o

o

Brain cooling to about 3-4°C below the baseline temperature (ie, to 33-34°C) may be neuroprotective. The optimal level of hypothermia for maximal neuroprotection is not known. Extreme hypothermia may cause significant systemic side effects. Up to 48-72 hours of cooling may be needed to prevent secondary neuronal loss. The greater the severity of the initial injury, the longer the duration of hypothermia needed for optimal neuroprotection.

Prevention o

o

Cooling must be begun early, within 1 hour of injury, if possible; however, favorable outcome may be possible if cooling is begun up to 6 hours after injury. A special device that selectively cools the head is now being tested in clinical studies; it is not available in the market. Some investigators believe that total body cooling (as done for open-heart surgery) may be superior to selective head cooling. The relative merits and limitations of different methods of brain cooling have not been studied.

Prevention o

Hypothermia may cause significant side effects, including coagulation defects, leukocyte malfunctions, pulmonary hypertension, and worsening of metabolic acidosis. Until more is learned, hypothermia remains an experimental modality

Prognosis 

Accurate prediction of the severity of long-term complications is difficult, although the following pointers may be used:

Prognosis •

•

Lack of spontaneous respiratory effort within 20-30 minutes of birth is associated with almost uniform mortality. The presence of seizures is an ominous sign. The risk of poor neurological outcome is distinctly greater in such infants, particularly if seizures occur frequently and are difficult to control.

Prognosis •

•

•

Abnormal clinical neurological findings persisting beyond the first 7-10 days of life usually indicate poor prognosis. Among these, abnormalities of muscle tone and posture (hypotonia, rigidity, weakness) should be carefully noted. Persistent feeding difficulties, which generally are due to abnormal tone of the muscles of sucking and swallowing, also suggest significant CNS damage. Poor head growth during the postnatal period and the first year of life is a sensitive finding predicting higher frequency of neurologic deficits.