Hypoxic Ischemic Encephalopathy

By

Perwin Aly Waly

Definition : -

It is abnormal neurobehavioral state in which the predominant pathogenic mechanism is impaired cerebral blood flow It is recommended to use HIE because this term accurately describes the clinical condition, encephalopathy from asphyxia, without implying the time of brain injury. It is also advised not using the terms perinatal asphyxia or birth asphyxia because it is difficult to identify the time of brain injury and nearly impossible to ascertain that the brain had been "normal" before such injury.

Medical/Legal Pitfalls:

Birth asphyxia, birth injury, and perinatal asphyxia are terms often used incorrectly to describe HIE.

Birth injury: is a condition in which fetal or neonatal injury

has occurred during the process of birth (ie, during the first and second stages of labor). Examples include brachial plexus injury; fracture of the clavicle; forceps-induced damage to the facial nerve or soft tissues; and cuts or bruises from scissors, clips, or scalp monitors.

Birth asphyxia:

is similar to birth injury in that asphyxia occurs during the first and second stages of labor when the fetus was otherwise normal.

Perinatal asphyxia:

signifies that asphyxia occurred at any time in the perinatal period, namely, from conception through the first month of life.

Pathophysiology:

Brain hypoxia and ischemia due to systemic hypoxemia, reduced cerebral blood flow (CBF) The initial compensatory adjustment to an asphyxial event is

*increase in the CBF due to hypoxia and hypercapnia.

*redistribution of cardiac output such that the brain receives an increased proportion of the cardiac output.

Additional factors that influence outcome :

*nutritional status of the brain

*severe intrauterine growth restriction

*preexisting brain pathology or developmental defects of the brain

*frequency and severity of seizure disorder that manifests at an early postnatal age (within hours of birth).

Mortality/Morbidity:

In severe HIE *mortality rate has been reported to be 50-75%

due to multiple organ failure or termination of care. *Some infants with severe neurologic disabilities

die in their infancy from aspiration pneumonia or systemic infections. Among the infants who survive severe HIE, the sequelae include

*mental retardation *epilepsy *cerebral palsy of varying degrees. The latter can

be in the form of hemiplegia, paraplegia, or quadriplegia.

The incidence of long-term complications depends on the severity of HIE.

*Up to 80% of infants who survive severe HIE develop serious complications

*10-20% develop moderately serious disabilities

*up to 10% are normal. Infants with mild HIE: tend to be free from serious CNS

complications but (15-20%) may have learning difficulties, even in the absence of obvious signs of brain injury.

Race: No predilection exists.

Sex: No predilection exists.

Age:

By definition, this disease is seen in the newborn period. Preterm infants can also suffer from HIE, but the pathology and manifestations are slightly different. Most often, the condition is noted in infants who are term at birth. The symptoms of moderate-to-severe HIE are almost always manifested at birth or within a few hours after birth.

History:

All of the following must be present for the designation of asphyxia:

Profound metabolic or mixed acidemia (pH <7.00) in an umbilical artery blood sample, if obtainedPersistence of an Apgar score of 0-3 for longer than 5 minutesNeonatal neurologic sequelae (eg, seizures, coma, hypotonia)Multiple organ involvement (eg, of the kidney, lungs, liver, heart, intestines)However, infants may have experienced asphyxia or brain hypoxia remote from the time of delivery and may have exhibited the signs and symptoms of hypoxic encephalopathy at the time of birth and, therefore, may not meet all of the criteria set forth by the AAP and ACOG

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.

The staging system proposed by Sarnat and Sarnat’s 1976 is often useful in classifying the degree of encephalopathy. Stages I, II, and III correlate with the descriptions of mild, moderate, and severe encephalopathy described below.

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 or mild HIE may be followed by sudden deterioration, suggesting ongoing brain cell dysfunction, injury, and death; during this period, seizure intensity might increase.

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.

*Disturbances of ocular motion, such as deviation of the

eyes, nystagmus, and loss of "doll's eye" (ie, conjugate) movements may be revealed by cranial nerve examination.

*Pupils may be dilated, fixed, or poorly reactive to light.

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 24-48 hours after onset.

Irregularities of heart rate and BP are common during the period of reperfusion injury.

Infants who survive severe HIE

The level of alertness improves by days 4-5 of life.

Hypotonia and feeding difficulties persist, requiring tube feeding for weeks to months.

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

Severely depressed respiratory and cardiac functions and signs of brainstem compression

Reduced myocardial contractility, severe hypotension, cardiac dilatation, and tricuspid regurgitation are noted frequently in severe HIE.

Patients may have severe pulmonary hypertension requiring assisted ventilation.

Renal failure presents as oliguria and, during recovery, as high-output tubular failure, leading to significant water and electrolyte imbalances.

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.

Lab Studies: No specific test can always confirm or exclude a diagnosis of HIE, since a diagnosis of HIE is made based on the history and physical and neurological examinations.

Serum electrolytes: In severe HIE cases, daily assessment of serum electrolytes are of value until the infant's status improved

*low serum sodium, potassium, and chloride *reduced urine flow and excessive weight gain may indicate acute

tubular damage or inappropriate antidiuretic hormone (IADH), particularly during the initial 2-3 days of life.

Similar changes may be seen during recovery, with increased urine flow, might indicate ongoing tubular damage and excessive sodium loss relative to water loss.

Renal function studies: Serum creatinine, creatinine clearance, and BUN

Cardiac and liver enzymes values are of value to assess the degree of hypoxic-ischemic injury to these other organs. These studies also provide some insight into injuries to other organs, such as the bowel.

Imaging Studies:Routine imaging studies may or may not consistently reveal abnormal findings. Therefore, a normal cranial imaging study does not rule out HIE.

Cranial ultrasound: Although ultrasound is portable and convenient, the findings in many HIE may be imprecise.

A CT scan of the head can be especially useful to confirm cerebral edema. It may shows zones of infarction or hemorrhage .

• MRI is valuable in moderately severe and severe HIE. However, the interpretation of MRI in infants requires considerable expertise.

Echocardiography: In infants requiring inotropic support, echocardiography (ECHO) helps to define myocardial contractility and the existence of structural heart defects

EEG: with its different types:

*Amplitude-integrated electroencephalography (aEEG) *Standard EEG *Traditional, multichannel EEG

Retinal and ophthalmic examination: This examination may be valuable, particularly as part of an evaluation for developmental abnormalities of the brain.

Special sensory evaluation: Screening for hearing is now mandatory due to increased incidence of deafness among infants with HIE that require assisted ventilation.

Treatment :-

Medical Care:

Seizures are generally self-limited to the first days of life but may significantly compromise other body functions, such as maintenance of ventilation, oxygenation, and blood pressure. Additionally, seizures should be treated early and be well controlled, since even asymptomatic seizures (ie, seen only on EEG) may continue to injure the brain. Seizures should be treated with phenobarbital or lorazepam; phenytoin may be added if either of these medications fails to control the seizures.

Other aspects of supportive care are outlined as follows:

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 inadequate hyperventilation, which may lead to severe hypoperfusion of the brain.

Maintain the blood gases and acid-base status in the physiological ranges including (PaO2), 80-100 mm Hg, (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 and glucose homeostasis should be achieved. 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 due to the high frequency of acute tubular necrosis and IADH.

When infants begin to improve, urinary output increases, and fluid administration must be adjusted.

For infants on high-frequency ventilators, the administered fluid volumes must be increased because, in those infants, venous return may be impaired, which affects cardiac preload.

Hypothermia is a new and evolving therapy in the mild-to-moderate cases of HIE.

Brain cooling

to about 3-4°C below the baseline temperature (i.e., 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.

The possible explanations of the mechanism of neuroprotection of the hypothermia are:

(1) reduced metabolic rate and energy depletion

(2) decreased excitatory transmitter release

(3) reduced alterations in ion flux

(4) reduced apoptosis due to HIE

(5) reduced vascular permeability, edema, and disruptions of blood-brain barrier functions.

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 .

Cooling must begin early, within 1 hour of injury, if possible; however, a favorable outcome may be possible if the cooling begins up to 6 hours after injury.

Two methods have been used in clinical trials for brain cooling. In selective head cooling, a cap (Cool-Cap) .The other method is to provide whole body hypothermia. The infant is placed over a commercially available cooling blanket.

But we must take in consideration the side effects of the hypothermia which include:

*coagulation defects *leukocyte malfunctions *pulmonary hypertension *worsening of metabolic acidosis *abnormalities of cardiac rhythm, especially during rewarming Diet: In most cases (particularly in moderately severe and severe

HIE)

*NPO during the first 3 days of life or until the general level of

alertness and consciousness improves. Begin trophic feeding with dilute formula or expressed

breast milk, about 5 mL every 3-4 hours.

Monitor abdominal girth and the composition of

stools and for signs of gastric retention; any of these may be an early indicator of necrotizing enterocolitis, for which infants with perinatal asphyxia are at high risk.

Medications :-

Providing standard intensive care support, *correcting metabolic acidosis, *limiting fluid intake to two-thirds the maintenance

volume for the first 3-4 days, *and seizure control are the main elements of

treatment. Anticonvulsants are the only specific drugs used often in this condition.

Treat seizures early and control them as fully as possible. Even asymptomatic seizures (i.e., seen only on EEG) may continue to injure the brain.

Continuation of seizure medications should depend on evolving CNS symptoms and EEG findings.

In most infants who are developing normally and have a normal EEG before hospital discharge, Phenobarbital is discontinued within 3-4 weeks of birth.

In those with significant CNS disability with or without persistent episodes of seizures, Phenobarbital is continued for 3-6 months; the decision to wean off the drug depends on later changes in EEG and clinical course.

Prevention:Most treatments discussed below are experimental:

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. Treated infants had fewer seizures (9 of 15) than untreated control infants (14 of 16). Treated infants also had fewer neurological deficits at age 3 years (4 of 15) than untreated infants (13 of 16).EAA antagonists:

an EAA antagonist(excitatory amino acids (EAAs), such as glutamate and aspartate), has shown promising results . This drug has serious cardiovascular adverse effects.

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

Lack of spontaneous respiratory effort within 20-30 minutes of birth is associated with almost uniform mortality.

The presence of seizures . The risk of poor neurological outcome is distinctly greater in such infants, particularly if seizures occur frequently and are difficult to control.

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.

An EEG done at about 7 days that has normal background activity is a good prognostic sign.

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.

References :-

American Academy of Pediatrics: Relation between perinatal factors and neurological outcome. In: Guidelines for Perinatal Care. 3rd ed. Elk Grove Village, Ill: American Academy of Pediatrics; 1992: 221-234. Berger R, Garnier Y: Pathophysiology of perinatal brain damage. Brain Res Brain Res Rev 1999 Aug; 30(2): de Haan HH, Hasaart TH: Neuronal death after perinatal asphyxia. Eur J Obstet Gynecol Reprod Biol 1995 Aug; 61(2):Depp R: Perinatal asphyxia: assessing its causal role and timing. Semin Pediatr Neurol 1995 Mar; 2(1):Gluckman PD, Wyatt JS, Azzopardi D, et al: Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicenter randomised trial. Lancet 2005; 365:Gluckman PD, Wyatt JS, Azzopardi D, et al: Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicenter randomised trial. Lancet 2005; 365:Gunn AJ, Gunn TR: The 'pharmacology' of neuronal rescue with cerebral hypothermia. Early Hum Dev 1998 Nov; 53(1):Hall RT, Hall FK, Daily DK: High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up. J Pediatr 1998 Feb; 132(2):Latchaw RE, Truwit CE: Imaging of perinatal hypoxic-ischemic brain injury. Semin Pediatr Neurol 1995 Mar; 2(1):