When a baby’s brain doesn’t receive enough oxygen and blood during or shortly after birth, the consequences can be life-changing. Treatment approaches for hypoxic-ischaemic encephalopathy focus on protecting the brain from further damage, managing symptoms, and supporting long-term development through a combination of emergency interventions and ongoing therapies.

What treatment aims to achieve in hypoxic-ischaemic encephalopathy

Treating hypoxic-ischaemic encephalopathy is about protecting a vulnerable brain at a critical moment and then supporting that child’s development over the months and years that follow. The main goals are to prevent additional brain injury, control symptoms like seizures, and help affected children reach their full potential despite the challenges they may face. Treatment decisions depend heavily on how severe the oxygen deprivation was, which parts of the brain were affected, and how quickly medical teams can intervene.^[1]

Healthcare providers grade HIE as mild, moderate, or severe, and this classification helps determine the most appropriate treatment path. Mild cases may resolve within days with supportive care alone, while moderate to severe cases require intensive interventions. The condition affects not just the brain but potentially other organs including the heart, kidneys, liver, and lungs, so treatment often addresses multiple systems simultaneously.^[2]

Medical guidelines from professional societies outline standard approaches, but research continues into new therapies that might improve outcomes. Some experimental treatments are being tested in clinical trials around the world, offering hope that future options may be more effective than what is currently available. The challenge is that brain injury from HIE evolves over hours and days after the initial oxygen deprivation, with damaged cells releasing toxic substances that harm neighbouring cells. This creates a window of opportunity for intervention, but also means that timing is absolutely critical.^[1]

Standard treatment approaches

Therapeutic hypothermia: cooling the brain

The most important treatment for moderate to severe HIE is therapeutic hypothermia, also called cooling therapy. This involves carefully lowering a baby’s body temperature to slow down the harmful processes that damage brain cells. The baby’s temperature is reduced to between 33 and 34 degrees Celsius (about 91 to 93 degrees Fahrenheit) and maintained at this level for 72 hours. This cooling must begin within six hours of birth to be most effective.^[11]

Cooling can be done in two ways. Whole-body cooling places the infant on a special cooling blanket or mattress. Selective head cooling uses a cap filled with circulating cold water placed on the baby’s head while the body is kept slightly warmer. Both methods aim to reduce the metabolic demands of brain cells, decrease inflammation, and interrupt the cascade of cell death that follows oxygen deprivation.^[13]

After 72 hours, the baby is slowly rewarmed over several hours. Rapid rewarming could cause additional problems, so this process is carefully controlled. During cooling and rewarming, medical teams monitor the baby constantly for complications such as changes in heart rate, blood pressure, or blood clotting. Some babies may experience temporary side effects including slow heart rate, low blood pressure, or increased bleeding risk, but these are typically manageable.^[13]

Studies have shown that therapeutic hypothermia can reduce mortality and the severity of long-term disabilities in babies with moderate to severe HIE. However, it doesn’t prevent all complications, particularly in the most severe cases. Not every baby is a candidate for cooling therapy. It’s typically reserved for infants born at or near full term (at least 36 weeks gestation) with moderate to severe symptoms of brain dysfunction.^[16]

Supportive care in the neonatal intensive care unit

Beyond cooling therapy, babies with HIE require comprehensive supportive care in a neonatal intensive care unit. This includes ensuring adequate oxygen levels and ventilation support. Some babies need help breathing and may be placed on a ventilator. Medical teams carefully balance oxygen delivery, as too little can worsen brain injury, but too much oxygen may also cause harm.^[11]

Blood pressure management is crucial because the brain needs steady blood flow to heal. Doctors may use medications called inotropes to support heart function and maintain appropriate blood pressure. These drugs help ensure that blood reaches all parts of the body, particularly the brain. Fluid management is also carefully controlled. Too much fluid can lead to swelling, including brain swelling, while too little can affect blood pressure and organ function.^[11]

Blood sugar levels require constant monitoring. Both low blood sugar (hypoglycaemia) and high blood sugar (hyperglycaemia) can worsen brain injury. Medical teams provide glucose as needed and adjust insulin if blood sugar becomes too high. Preventing fever is another priority. Even mild increases in body temperature after HIE can worsen outcomes, so any fever is treated promptly.^[11]

Seizure management

Seizures are common in babies with HIE, occurring in up to 50% of moderate to severe cases, typically within the first 24 hours after birth. These seizures represent abnormal electrical activity in the injured brain and need to be controlled because ongoing seizures can cause additional brain damage.^[7]

The first-line medication for seizures in newborns with HIE is usually phenobarbital, a drug that reduces abnormal electrical activity in the brain. If phenobarbital doesn’t adequately control seizures, doctors may add other medications such as phenytoin, levetiracetam, or midazolam. These medications work through different mechanisms to calm overactive brain cells.^[11]

Continuous monitoring with electroencephalography (EEG) helps medical teams detect seizures, as many are not visible on the outside. This allows for prompt treatment adjustments. In some cases, after the acute period has passed and seizures are controlled, medication can be gradually reduced or stopped before the baby goes home. However, some children may need ongoing seizure medication, and follow-up with a paediatric neurologist is typically recommended.^[11]

Nutritional support and feeding

Babies with HIE often have difficulty feeding due to weak muscles in the mouth and throat or because they are too unwell to feed normally. Initially, nutrition is provided through an intravenous line. As the baby’s condition stabilizes, feeding through a tube that goes through the nose into the stomach may be started. Eventually, the goal is to transition to breast milk or formula feeding by mouth, though this progression depends on the baby’s neurological recovery and ability to coordinate sucking, swallowing, and breathing.^[9]

Transfer to specialized centres

Because therapeutic hypothermia must begin within six hours of birth and requires specialized equipment and expertise, babies born in hospitals without these capabilities often need urgent transfer to a tertiary neonatal intensive care unit. These specialized centres have the technology for cooling therapy, continuous EEG monitoring, advanced neuroimaging, and consultations with paediatric neurologists. Even if the six-hour window has passed, transfer may still be beneficial because these centres offer comprehensive care and better resources for managing complications.^[11]

Treatment approaches being studied in clinical trials

While therapeutic hypothermia has improved outcomes for many babies with HIE, it doesn’t help everyone, particularly those with severe brain injury. Researchers around the world are testing new treatments that might be used alone or combined with cooling therapy to provide better protection for damaged brains. These experimental approaches target different mechanisms of brain injury and repair.

Erythropoietin and related compounds

Erythropoietin is a hormone naturally produced by the body that stimulates red blood cell production. Researchers discovered that it also has neuroprotective properties, meaning it can help protect brain cells from damage and may even promote brain repair and regeneration. In animal studies, erythropoietin reduced brain damage after oxygen deprivation, which led to clinical trials in human infants.^[16]

Several Phase II clinical trials have investigated giving erythropoietin to babies with HIE, often in combination with cooling therapy. Early results suggest this approach is safe and may improve neurodevelopmental outcomes. Some studies have shown that babies receiving erythropoietin had better motor function and cognitive development at one and two years of age compared to those receiving cooling alone. The medication is typically given as injections during the first week of life.^[16]

Large Phase III randomized controlled trials are currently underway in the United States and other countries to definitively determine whether erythropoietin improves outcomes when added to standard cooling therapy. These trials involve hundreds of infants and will provide more conclusive evidence about the benefits and optimal dosing of this treatment. Related compounds called erythropoietin analogues are also being investigated as they may have similar or better neuroprotective effects.^[16]

Melatonin

Melatonin is a hormone that regulates sleep-wake cycles, but it also has powerful antioxidant and anti-inflammatory properties. After brain injury from oxygen deprivation, harmful molecules called free radicals damage cells. Melatonin can neutralize these free radicals and reduce inflammation in the brain. In laboratory studies and animal models of HIE, melatonin reduced brain damage and improved outcomes.^[16]

Small clinical trials have tested melatonin in newborns with HIE, usually in combination with therapeutic hypothermia. Results have been promising, with studies showing reduced markers of brain injury in blood tests and better outcomes on brain imaging. Melatonin appears safe when given to newborns and crosses easily into the brain where it can exert protective effects. Larger trials are needed to confirm these findings and establish the best dose and timing.^[16]

Xenon gas

Xenon is a noble gas that has anaesthetic properties but also appears to protect brain cells from damage. It works by blocking certain receptors in the brain that become overactive after oxygen deprivation and contribute to cell death. When combined with cooling therapy in animal studies, xenon provided better brain protection than cooling alone.^[16]

Clinical trials have tested xenon inhalation in babies with HIE. The gas is delivered through a breathing circuit while the baby undergoes cooling therapy. Some studies showed promise, but results have been mixed. One challenge is that xenon is expensive and requires specialized delivery systems. Researchers continue to investigate whether xenon might benefit certain subgroups of babies with HIE and whether the timing or duration of administration needs adjustment.^[16]

Argon gas

Like xenon, argon is a noble gas with potential neuroprotective properties. It’s less expensive than xenon and may work through similar mechanisms to reduce brain cell death after oxygen deprivation. Animal studies have shown protective effects, and early-phase clinical trials are beginning to test argon inhalation in human infants with HIE. More research is needed to determine safety and effectiveness.^[16]

Allopurinol

Allopurinol is a medication commonly used to treat gout in adults, but it also acts as an antioxidant. It reduces the production of free radicals that damage brain cells after oxygen deprivation. Researchers have investigated giving allopurinol to pregnant women during labour when foetal distress is detected, with the idea that the drug would reach the baby and provide protection during delivery. Some studies have also tested giving allopurinol directly to newborns after birth.^[16]

Results from clinical trials have been mixed. Some studies showed reduced markers of brain injury, while others didn’t demonstrate clear benefits on long-term outcomes. The optimal timing and dosing remain unclear. Further research is exploring whether allopurinol might be beneficial in specific situations or when combined with other treatments.^[16]

Magnesium sulfate

Magnesium sulfate is widely used to prevent seizures in women with preeclampsia and to protect the brains of premature babies. It may also have neuroprotective effects in term infants with HIE. Magnesium blocks certain brain receptors that become overactive after oxygen deprivation and can also reduce inflammation. Clinical trials have investigated giving magnesium sulfate to newborns with HIE alongside cooling therapy, with some showing potential benefits, though more research is needed to establish its role.^[16]

Stem cell therapy

Stem cell therapy represents an exciting but still experimental approach for treating HIE. Stem cells have the potential to develop into different cell types and can release substances that promote healing and reduce inflammation. Different types of stem cells are being studied, including those derived from umbilical cord blood, bone marrow, and other sources.^[16]

The idea is that these cells, when given to a baby with brain injury, might migrate to damaged areas and help repair tissue or create an environment that supports the brain’s own healing processes. Early-phase clinical trials are testing the safety of stem cell administration in babies with HIE. While results are preliminary, some studies suggest these cells can be given safely and may improve outcomes. Much more research is needed to understand which types of stem cells work best, when they should be given, and how many cells are needed.^[16]

Remote ischaemic postconditioning

Remote ischaemic postconditioning is a fascinating approach that involves briefly restricting and restoring blood flow to a limb (usually the leg) after a brain injury. This triggers protective signals in the body that can reduce damage to distant organs including the brain. The procedure is simple and non-invasive, typically involving inflating a blood pressure cuff on the baby’s leg for short periods. Small studies have tested this technique in combination with cooling therapy, with some showing potential benefits. Larger trials are needed to confirm these findings.^[16]

Where trials are conducted

Clinical trials for new HIE treatments are being conducted at specialized medical centres around the world, including in the United States, Canada, various European countries, and other regions. Many of these trials are multicentre studies, meaning they involve several hospitals working together to enrol enough patients. Eligibility criteria vary by trial but typically include babies born at term or near-term with evidence of moderate to severe HIE. Parents interested in trial participation can discuss options with their baby’s medical team, who can provide information about available studies at their institution or nearby centres.^[16]

Most common treatment methods

• Therapeutic hypothermia (cooling therapy)
  • Body or head cooling to 33-34°C for 72 hours, started within 6 hours of birth
  • Reduces metabolic demands and interrupts cascade of brain cell death
  • Standard care for moderate to severe HIE in term or near-term infants
  • Followed by careful rewarming over several hours
• Respiratory support
  • Oxygen supplementation to maintain appropriate levels
  • Mechanical ventilation for babies unable to breathe adequately on their own
  • Careful monitoring to avoid both too little and too much oxygen
• Blood pressure and perfusion management
  • Inotropic medications to support heart function and blood pressure
  • Careful fluid management to prevent both dehydration and fluid overload
  • Continuous monitoring to ensure adequate blood flow to brain and other organs
• Seizure control
  • Phenobarbital as first-line medication for seizures
  • Additional medications such as phenytoin, levetiracetam, or midazolam if needed
  • Continuous EEG monitoring to detect and manage seizures
  • Gradual reduction or discontinuation of medications after acute period in some cases
• Metabolic and nutritional support
  • Blood glucose monitoring and management to prevent both low and high levels
  • Initial intravenous nutrition, progressing to tube feeding and eventually oral feeding
  • Prevention and treatment of electrolyte imbalances
• Experimental neuroprotective therapies (in clinical trials)
  • Erythropoietin and analogues to protect brain cells and promote repair
  • Melatonin for antioxidant and anti-inflammatory effects
  • Noble gases (xenon, argon) to reduce brain cell death
  • Allopurinol as an antioxidant
  • Magnesium sulfate for neuroprotection
  • Stem cell therapy to promote healing and tissue repair
  • Remote ischaemic postconditioning to trigger protective signals
• Long-term developmental support
  • Physical therapy to address motor development and muscle tone issues
  • Occupational therapy for daily living skills and fine motor function
  • Speech and language therapy for communication and feeding difficulties
  • Early intervention programmes for developmental delays
  • Regular follow-up with neurologists and developmental specialists