Stages of Hypoxic-Ischemic Encephalopathy (HIE)

Stage 1 hypoxic-ischemic encephalopathy generally resolves without secondary injuries, but infants with stages 2 and 3 HIE generally experience a predictable chain reaction of events that stem from the initial deprivation of oxygen and loss of blood flow to the brain. 

Primary Energy Failure 

The purpose of blood flow is to deliver nutrients to all body parts. Oxygen and glucose are two of the most important nutrients that provide the brain with energy. The brain is deprived of both substances during primary energy failure, also known as the acute phase of hypoxic-ischemic encephalopathy.   

As a result, the brain becomes deficient in adenosine triphosphate (ATP), which essentially powers the brain.  

This triggers lactic acid production as the body attempts to provide the brain with an alternative energy source. Lactic acid causes blood vessels to dilate, leading to brain swelling. Lactic acid also leads to a failure of the body’s sodium potassium pump, resulting in excess calcium entering the cells. 

Excess intracellular calcium causes a series of chemical reactions in the brain that ultimately lead to excess fluid in the brain, DNA fragmentation, restricted blood flow to the brain, and cell death. 

In moderate and severe HIE, the buildup of reactive oxygen species in the tissues, also known as free radicals, damages the brain and other vital organs. Multiorgan dysfunction is common in moderate and severe hypoxic-ischemic encephalopathy cases, most commonly impacting a combination of the following organs:   

• Heart 
• Lungs  
• Kidneys 
• Liver 
• Blood 

One of the primary drivers of multiorgan failure in HIE is low blood pressure, which affects approximately 62 percent of HIE patients, according to Frontiers in Pediatrics. 

Cell Death 

Two types of cell death occur during primary energy failure: necrosis and apoptosis.  

Necrosis occurs when cells swell and rupture. This results in the destruction of the cellular membrane and a subsequent release of the cellular contents into the surrounding area. This increases inflammation. Necrosis is most prevalent in Stage 3 HIE. 

Apoptosis occurs when cells shrink and die without damaging the cellular membrane or causing inflammation. While apoptosis is a less damaging process, both apoptosis and necrosis can lead to impaired brain function. 

The Latent Period 

The latent phase of HIE is a period of recovery that occurs in stage 2 and 3 HIE patients. It is characterized by a restoration of blood flow to the brain. It may last one to six hours. If the infant is a candidate for therapeutic interventions, the optimal timing is generally during this stage.  

During this period, blood, oxygen, and nutrients are reintroduced into the brain tissues, and the brain returns to normal oxygen consumption. However, the damage done during primary energy failure is still present, and neuroinflammation and cell death reactions continue. Inevitably, the latent period gives way to secondary energy failure. 

Secondary Energy Failure 

Secondary energy failure occurs approximately six to 48 hours after the acute stage in stage 2 and 3 HIE cases. The damaging effects are often more severe than during primary energy failure. However, the initial injury’s severity influences this phase’s severity. 

During secondary energy failure, the brain experiences an additional injury known as reperfusion or hyperperfusion, which involves an excessive blood flow to the brain. The exact mechanisms responsible for this stage are still under investigation, but researchers believe the following mechanisms are responsible: 

• Angiogenesis – the formation of new blood vessels immediately following the initial injury 
• Cerebral vasodilation – an increase in the diameter of the blood vessels in the brain 
• Oxidative stress – the presence of too many unstable molecules known as free radicals as a result of oxygen deprivation 
• Excitotoxicity – overstimulation caused by an excess of the neurotransmitter glutamate 
• Inflammation – leads to edema due to the influx of white blood cells in the brain tissues 

Oxidative stress is typically managed by antioxidants, which fight off free radicals, but newborn infants have a low level of antioxidants in the brain. At the same time, they consume more oxygen as a result of the transition to life outside the womb.  

Excitotoxicity may lead to excess sodium and calcium in the cells, leading to long-term impairments of the following: 

• Hearing 
• Vision 
• Somatosensory function 
• Learning 
• Memory 
• Child development 

The damage caused by this stage ultimately leads to increased cell death and sets the stage for injury to other bodily organs.  

The Tertiary Phase of Moderate and Severe HIE  

The tertiary phase occurs during the weeks and months following secondary energy failure. The baby’s alertness may improve approximately four to five days following the initial injury, and the brain attempts to repair and remodel itself. The brain may continue to experience damage for months to years.  

Normal brain development during the early years of a child’s life is characterized by a rapid increase in neurons and synapses as the child learns and adapts to the world. Neural plasticity is the brain’s ability to form new pathways to facilitate adaptation. It is most pronounced during infancy and early childhood.  

The brain damage caused by moderate and severe HIE can inhibit the development of new neurons and reduce plasticity. This can cause ongoing brain damage and impaired development. 

Children with moderate to severe HIE may continue to have reduced muscle tone and associated difficulties with feeding, resulting in a need for tube feeding for weeks or months.