Hypoxic-Ischemic Encephalopathy

Hypoxic-Ischemic Encephalopathy (HIE) is the term used to describe the resultant condition due to a deficit in oxygen supply to the brain.  The perinatal brain can be deprived of oxygen by two major pathogenetic mechanisms: hypoxemia and ischemia

  •  Hypoxemia - a diminished amount of oxygen

  •  Ischemia - a diminished amount of blood perfusing the brain

  •  Encephalopathy - any dysfunction of the brain

Hypoxemia and ischemia can occur as a result of an event either before and/or during delivery, such as a nuchal cord, placentia previa, abruptio placentae, prolapsed or compressed cord, ruptured uterus, and/or obstetric accident.   These conditions can lead to reduced oxygen and/or blood flow to the infant.  Not all cases of hypoxic-ischemic insult before and/or during labor will result in HIE.

 In instances of HIE, following the termination of the insult, a cascade of deleterious events result in cell death.  Two fundamental modes of cell death occur.  They are necrosis and apoptosis.  Hypoxic ischemic insults may lead to necrosis or apoptosis, or both, depending on the severity of the insult, the local environment of the affected region of the brain, and the maturational state of the brain cell. 

 Necrosis – occurs during and for a period following the injury and is characterized by cell swelling, membrane disintegration, cell rupture, release of intracellular contents, and as a consequence, inflammation and phagocytosis.  

 Necrotic cell death then triggers a series of biochemical cascades.   During the next 24-48 hours, a secondary energy failure initiates, leading to apoptotic cell death.

 Apoptosis – is a secondary energy failure starting within ~ 24 hours of birth and may last for more than 48 hours.  It is characterized by cell shrinkage, relative preservation of the cellular membrane, and death without inflammation.  Apoptotic cell death requires the activation of specific death genes - cell suicide.

 HIE is a progressive injury developing over hours to days.  There are two major areas of the brain that can be affected by the asphyxial event and the resultant hypoxia and/or ischemia.  They are the cortical “watershed” area, and the deep structures – the basal ganglia and thalamus.


The basal ganglia and the motor cortex control movement.  Communications run through the thalamus.  Depending on the severity and area of the brain injured, HIE can result in a wide variety of disorders including:

  •  Hearing loss

  • Learning disability

  • Mild motor dysfunction

  • Cerebral palsy

  • Severe motor dysfunction

  • Death


The clinical characteristics of HIE can be described as mild, moderate, or severe.  The most common grading or staging system is by the Sarnat scale developed by Sarnat and Sarnat in 1976.  The Sarnat Score combines clinical and EEG findings (I, II, III = mild, moderate, severe).  When using only clinical findings, this grading system is called the Modified Sarnat Score. 


Mild HIE – Sarnat Stage I

  • Hyper-alert

  • Eyes wide open

  • Does not sleep

  • Irritable

  • No seizures

  • Usually lasts < 24 hours


Moderate HIE – Sarnat Stage II

  • Lethargy (difficult to rouse)

  • Reduced tone of the extremities and/or trunk

  • Diminished brainstem reflexes (pupil/gag/suck)

  • Possible clinical seizures


Severe HIE – Sarnat Stage III

  •  Coma (cannot be roused)

  • Weak or absent respiratory drive

  • No response to stimuli (may have spinal reflex to painful stimuli)

  • Flaccid tone of the extremities and trunk (floppy)

  • Diminished or absent brainstem reflexes (pupil/gag/suck)

  • Diminished tendon reflexes

  • EEG severely abnormal (suppressed or flat EEG with or without seizures)


Outcomes of babies with HIE vary according to the severity of the injury.   The outcomes range from normal to disability to death.  The moderate cases result in ~40-70% death or disability with more cases of disability than death.  The disabilities may include cerebral palsy, cognitive deficits, and seizures.  The severe cases almost always result in death or disability with more cases of death than disability.  The disabilities may include mental retardation, severe motor dysfunction, and seizures. 


Traditional treatment of HIE has been supportive care – management of ventilation, vasopressive support, hemodynamics, and seizures.   Selective head cooling with the Olympic Cool-Cap System is now an option for babies meeting certain criteria (discussed below) and is the only U.S. FDA approved treatment of neonatal HIE.  


How does Selective Head Cooling with the Cool-Cap System work?

 There is a therapeutic window of opportunity during which hypothermic intervention can decrease the amount of cell death resulting from secondary energy failure.  If selective brain cooling can be initiated during the first 6 hours after the injury and the baby’s brain is kept cool for the duration of the secondary energy failure state, science has demonstrated selective head cooling can interrupt the second phase of the injury and have a significant effect on the severity of the secondary cell death.  Further, animal studies have also shown that if selective head cooling is started sooner (<3 hours) results are even more significant. 

 Selective head cooling with the Olympic Cool-Cap System utilizes a sealed water cap placed over the infant’s head that is cooled to maintain a core rectal temperature of 34.5°C ± 0.5ºC over a 72 hour treatment period followed by a 4-hour passive rewarming period.  The Cool-Cap System generates a temperature gradient across the brain.  As a result, the outer area of the brain, the cortex, is cooler than the deep brain structures.  Research has shown that optimal neuroprotective temperatures for the cortex are colder than neuroprotective temperatures for the deep brain structures. 

 During the selective head cooling treatment with the Olympic Cool-Cap System, the infant experiences mild systemic hypothermia and receives warmth through the radiant warmer.  The goal is to adjust the cap water appropriately in order to maintain the infant’s core rectal temperature at 34.5°C + 0.5ºC (34.0ºC – 35.0ºC).  By selectively cooling only the head with mild systemic hypothermia, infants are less likely to experience the side effects seen with whole body cooling.  These side effects may include:  lower platelet count, longer dependence on pressors, higher prothrombin times, and increased need for plasma and/or platelet transfusions. 

There are two expected benign side effects associated with selective head cooling (although not all babies will experience these side effects).  The first is minor cardiac arrhythmias.  Sinus bradycardia is known to be associated with hypothermia. The second side effect is head or scalp edema, which generally resolves with no action, or with scalp massage, through adjustments to the cooling cap, or by positioning.


Selection Criteria for selective head cooling with the Olympic Cool-Cap System

 Once an infant has suffered a hypoxic and/or ischemic event, selective head cooling with the Olympic Cool-Cap System may be considered for treatment to prevent or reduce the severity of neurological injury associated with HIE for an infant that is:

 Full-term infant with clinical evidence of moderate to severe hypoxic-ischemic encephalopathy (HIE) as defined by criteria A, B, and C:

 Criteria A

  •  Infant at > 36 weeks gestational age and at least one of the following:

  • Apgar score < 5 at 10 minutes

  • Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth

  • Acidosis defined as either umbilical cord pH or any arterial pH < 7.00 within 60 minutes of birth

  • Base deficit > 16 mmol/L (or Base excess < - 16 mmol/L) in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood)


Criteria B

 Infant with moderate to severe encephalopathy consisting of altered state of consciousness (as shown by lethargy, stupor, or coma) and at least one of the following:

  • Hypotonia

  • Abnormal reflexes, including oculomotor or papillary abnormalities

  • Absent or weak suck

  • Clinical seizures


Criteria C

 Infant has an amplitude-integrated encephalogram/cerebral function monitor (aEEG/CFM) recording of at least 20 minutes duration that shows either moderately/severely abnormal aEEG background activity (score of 2 or 3 – see additional supportive information for HIE Scoring Technique) OR seizures.


If all three criteria are met, selective head cooling with the Olympic Cool-Cap System should be started within six hours of birth.  Whenever possible, treatment should be started as early as possible.


Contraindications include:

  • Imperforate anus

  • Evidence of head trauma or skull fracture causing major intracranial hemorrhage

  • Birth weight < 1,800 grams



 Treatment Parameters

 When following the criteria and treatment parameters, selective head cooling with the Cool-Cap System is FDA approved and safe for the treatment of HIE. 




Effects of hypothermia

 Hypothermia has been known to:

  •  Prolong the half-lives of medications

  • Inhibit antimicrobial activity

  • Create anticoagulant effects

 Care should be taken to monitor these conditions.



 Significant overcooling (~32ºC) may result in a shut down of the infant’s peripheral circulation and the infant will no longer be taking in body warmth from the radiant warmer.  Infants should be carefully rewarmed to the target range by removal of the cooling cap before cooling is resumed.

 Rewarming rate should not exceed 0.5ºC per hour to prevent vasodilation, hypotension, and possible seizures (as seen in some animal studies).




Laboratory Considerations

  •  Monitor and correct all blood gases and pH values for core temperature


General Infant Care

 Do not initiate oral feeding during treatment


Potential Adverse Effects of Hypothermia

  • Increased oxygen consumption

  • Transient hyperglycemia

  • Prolongation of the QT interval

 Care should be taken to monitor these conditions especially when administering medications that would further prolong the QT interval or increase the effects of hyperglycemia.


Skin Integrity

  • Use selective head cooling only on unbroken skin or covered lesions

  • Use only the scalp sensor under the water cap

  • Maintain at least 12 hour scalp checks


Pausing Treatment

 Physiological and cap alarms are inactive when the system is paused.


Radiant Warmer

  • Do not set the radiant warmer above 37.5ºC



Larger infants may require less heat to re-warm or may re-warm faster than 0.5ºC per hour.  Closely monitor these infants.  Do not attempt re-cooling to slow down the rate of re-warming.