Research Update: Increasing the Effectiveness of Hypoxic Ischemic Encephalopathy (HIE) Treatment

Brain research is an ongoing process, and, at the moment, hypothermia therapy (using a cooling cap, cooling pad, or cooling blanket) is the standard of care when it comes to hypoxic ischemic encephalopathy. Additive or supplemental measures in addition to hypothermia are still in preclinical or clinical trials, so it is too early to say whether any of these supplemental measures will be adopted as standards of care. Because these are highly experimental findings, we caution readers that we are merely providing this information as an update on findings in the field of HIE research, rather than as a potential source of treatment information. Research has shown some of the results to be inconclusive while others show promise.

There are numerous therapies being tested to determine whether they are effective for HIE treatment. Some of these are tested in conjunction with hypothermia therapy, which is the standard of care in helping the brains of neonates prevent damage after a hypoxic-ischemic injury. Because the cascade of events in these injuries is very complex, researchers are focusing on multiple parts of the cascade process to figure out different places where damage can be mitigated. The following is a listing of some of the recent topics of research that have been identified as areas of interest in HIE treatment.

Areas of Research in HIE Treatment

NMDA Receptor Antagonists (Magnesium, Xenon)

Magnesium and HIE

Magnesium is known to be safe, and is already given to women with preeclampsia and/or preterm labor who have not yet given birth to confer neuroprotective effects on their babies. It is also used to help protect the brains of babies who are at imminent risk of preterm birth. Magnesium has been extensively studied in both animal models and in human neonates.

Research shows that administration is effective, though the timing is crucial – when administered in a non-human model at one versus two hours after injury, the neuroprotective effect was markedly less after two hours. In human studies, magnesium is safe, well-tolerated, and shows a predominance towards improvement. Researchers state that magnesium may  have an additive effect in combination with hypothermia therapy, though more research is needed about the two in combination.

Xenon and HIE

Xenon is a NMDA receptor antagonist like magnesium, and is currently used as an inhaled anesthetic. Non-human testing shows that hypothermia and xenon are effective separately, but are even more effective together. Timing and dosage are crucial. Treatment is more effective the sooner it is administered, and dosage must be carefully balanced so as not to cause respiratory depression and other unwanted effects. More research is needed into the proper duration and timing of treatment. Unfortunately, this treatment is very expensive, limiting its usefulness. Additional human studies are underway.

Erythropoietin (EPO) and HIE

Erythropoietin, which is used to stimulate red blood cell production, has neuroprotective benefits in infants with anemia of prematurity. When premature infants were treated with EPO, the EPO decreased IVH and white matter injury and improved neurodevelopmental scores. EPO also had protective effects in other neurological injuries, including spinal cord injury, traumatic brain injury, and ischemic stroke.

Non-human studies demonstrate that EPO alone does have neuroprotective effects, though human data on EPO in relation to HIE is limited. In infants with mild to moderate HIE, EPO reduced seizures and improved neurodevelopmental outcomes at 6 months. With moderate/severe HIE without hypothermia therapy, those treated with EPO had better neurological scores at 1, 2, and 3 weeks after birth. However, there were differences in outcomes between those with moderate and those with severe HIE. In cases where infants had moderate HIE, the incidence of death and moderate/severe disability incidence at 18 months was lower. This benefit did not extend to severe HIE.

Also, recent studies show limited evidence for EPO’s additive effect on hypothermia therapy, and also note that it is difficult to extrapolate the results of some preclinical trials because some of the protocols commence treatment much earlier than in human randomized controlled trials.

EPO is considered promising because apoptotic injury can continue for weeks after the initial injury incident, and neurogenesis takes a long time. EPO specifically targets these injuries and can be administered for longer than other treatments. Clinical trials of combination EPO and hypothermia therapy are still ongoing.

Stem Cell Therapy and HIE

Stem cell therapy is a relatively new concept but shows some promise for treating neonatal brain injury, since it addresses several different mechanisms of hypoxic ischemic injury. It seeks not only to replace damaged cells but also to produce anti-inflammatory effects that help to preserve existing tissues. Researchers are still in the process of unraveling the cellular mechanisms behind stem cell therapy, so it will likely be some time before such a therapy reached broad-scale clinical trials.

There are several benefits to stem cell therapy in terms of the way that cells are delivered and how they differentiate, as indicated by preclinical non-human studies. When there is an injury, the cells migrate over to the injured area (even from the other side of the brain) and differentiate into several kinds of cells.  If successful, this could help not just with the replacement of lost neurons but also in remyelination. Stem cell transplantation also decreased the amount of gray matter and white matter loss, and (when delivered via IV or intracranial injection) decreased the amount of injury in the hippocampus, one of the areas most sensitive to hypoxic-ischemic injury. Even if the rate of survival of the transplanted cells is comparatively low, stem cells may provide other very important benefits, such as better motor and behavioral outcomes. Functional testing in preclinical tests showed improvement, even with the limited restoration of brain volume. Stem cells decrease the number of microglia present, which is important because microglia are part of the inflammatory process.

Because this is a realm of research still in a very early experimental phase, there are many questions that researchers have yet to answer. These include:

  • Best type and source of cells to use
  • How to best administer cells
  • Whether to use immunosuppressives with stem cell therapy
  • Amount of cells to use
  • Timing
  • How stem cell therapy will interact with hypothermia therapy
  • How effective stem cell therapy is

Overall, trials are still underway, and much research will be needed before coming to a conclusion regarding if, how and when to use stem cells as a therapy for brain injury.

N-Acetylcysteine (NAC) and HIE

NAC is most well-known for its use in treating adult liver injury after acetaminophen overdose. It is known to decrease reperfusion injury and reduce NO production in adults. When applied to spinal cord injuries, NAC and hypothermia together improved the degree of injury. Neonatal rat studies demonstrated that NAC reduced the area of damage and inhibited apoptosis.

Current studies into NAC are limited but promising. One study that looked at NAC in conjunction with hypothermia therapy found that they reduced injury size 48 hours after the incident and preserved brain volume after 2 and 4 weeks. However, more studies are needed into combination therapy and the use of NAC in humans, as well as the proper dosage and length of treatment.

Melatonin and HIE

While melatonin is widely known for its use in regulating sleep, it has other uses, including free radical scavenging. It decreases inflammatory cytokines and stimulates antioxidant enzymes, and can also cross the blood-brain barrier  and decrease microglial activation. In adults, it has improved outcomes for stroke, while in infants, it has been used to reduce inflammation from sepsis with no adverse effects.

Both human and animal models show that melatonin administration reduced oxidative stress and glial cell activation. The benefit was measurable when melatonin was administered before or after the injury, and the amount of benefit was dose-dependent.

Overall, melatonin has a significant amount of evidence backing it as a safe neuroprotective therapy, but further studies need to be done into optimal timing, dosage and delivery method, as well as how it specifically interacts with hypothermia therapy. Two recent studies have looked at melatonin in conjunction with hypothermia therapy and concluded that it is feasible and may ameliorate brain injury to a degree.

Anticonvulsants and HIE

Anticonvulsants are under study as neuroprotectants for several reasons. First, babies with hypoxic-ischemic injury have a greater chance of developing seizures, and seizures can make brain damage worse. Preventing or reducing seizure rate helps reduce the brain injury associated with those seizures.

There are three anticonvulsants that have been studied for this purpose:

Topiramate and HIE

Some preclinical studies showed that topiramate and hypothermia together decreased the severity of brain damage and improved function one and four weeks after the injury. This is significant because some health centers may not have in-house cooling centers. They must instead provide rapid transportation to facilities that do. Using topiramate can extend the window of time in which cooling will be effective, allowing treatment to be maximally effective even within a longer timeframe.

When given in one of two ways: (1) before and after injury or (2) after injury only, topiramate improved neuroprotection and long-term outcomes in an animal model, though the best outcomes were in the population who were treated before the injury. Few studies have been conducted in humans thus far, though one has shown that there was no statistically significant difference in short-term outcomes, survival rate or pathology on MRI between a control group and a group that received hypothermia and topiramate.

Levetiracetam and HIE

This drug is a first-line anticonvulsant in children and operates using pathways similar to topiramate. One study shows that it improved outcomes in focal ischemia but not in global insults, while another showed that it did not have a neuroprotective effect in in-vitro cell studies (unlike some other anti-seizure medications). No studies have been conducted specifically regarding neonatal hypoxic ischemic encephalopathy.

Phenobarbitol and HIE

This drug is the current drug of choice for handling neonatal seizures. While it does decrease cell death in vitro after oxygen/glucose deprivation, it has some potential negative side effects, such as long term impact on the liver and kidneys. Preclinical studies show an increased incidence of spatial learning deficits while other studies show that it may induce cognitive impairment in infants and toddlers. Studies about how well phenobarbital works to protect the brain (either alone or together with hypothermia) show mixed results.

Overall, anticonvulsants have many benefits and are under continued study. Because they are already extensively prescribed for infants and children, data on proper dosing is already available. Anticonvulsants’ anti-seizure properties are beneficial for HIE treatment given that seizures make brain damage worse, but further research is still needed to determine effectiveness and potential negative side effects on the developing brain.

Antioxidants and HIE

After a hypoxic ischemic injury occurs, damage continues even after the initial event is over. Studies are examining the role of antioxidants in preventing or reducing this secondary stage of brain injury. Antioxidants are a very broad category of substances, and can include Vitamins A, C, and E, selenium, copper, zinc and manganese, as well as flavonoids, phenols and polyphenols.

Polyphenols and HIE

There are many different polyphenols. One of these is resveratrol, which can be found in pomegranate juice. There are two trials that look at the effect of polyphenols as neuroprotectants for neonates. An animal model showed that supplementing a maternal diet with pomegranate juice during the last ⅓ of pregnancy and during suckling protected offspring better than just water, sugar water or Vitamin C water. The protective effect depended on dosage levels. A later study built off these results, seeking to prove that it was specifically the polyphenols in the pomegranate juice that caused this neuroprotective effect. It suggested that this was indeed the case.

Ascorbic Acid (Vitamin C) and HIE

Vitamin C is a well-known antioxidant. In preclinical studies, studies have demonstrated Vitamin C’s effectiveness as a neuroprotectant. It has also been evaluated individually and in combination with other compounds such as alpha-tocopherol. Both have modest effects individually but together restored mitochondrial activity to 91% of normal controls after transient intrauterine ischemia. Although non-human studies seem promising, human studies of Vitamin C and ibuprofen together failed to show such neuroprotective effects.

Allopurinol and HIE

Allopurinol has been studied for many years for preventing and treating cerebral hypoxia ischemia, with very conflicting results. Animal studies showed that allopurinol was effective in reducing markers such as tissue swelling and neurological deficits, and was able to cross the placenta to reach therapeutic blood levels, but the results of human studies were not so clear cut.

Overall, antioxidant studies show mixed results but are still worthy of further study.

Tetrahydrobiopterin (BH4) and HIE

Previous studies have demonstrated that BH4 can improve functionality in patients with dystonia, which indicates it may have a role in preventing motor problems. Studies show that HI injury decreases BH4 levels, making the brain more susceptible to injury. In an animal model, bringing up BH4 levels reduced this risk. Maternal treatment with BH4 decreased the incidence of motor deficits and the number of stillbirths. In mice with intracerebral hemorrhage, however, neurological outcomes after 24 hours showed no benefit.

BH4 has potential for both maternal and neonatal administration due to its role in determining how vulnerable the brain is to injury. However, research has not yet studied how BH4 interacts with hypothermia, nor do we know the best dosing route and schedule or appropriate length of treatment.

Hydrogen Sulfide (H2S) and HIE

H2S can induce suspended animation, which can decrease energy expenditure, preventing further damage from occurring. It protects lung, liver, kidney and heart tissues after ischemia-reperfusion injury, but research has occurred only in non-human models and is controversial at best. H2S is toxic at high concentrations but beneficial at low concentrations, and is a pulmonary irritant when inhaled (though it can be administered via IV). More studies into H2S are recommended.


Legal Help for HIE Treatment

logo 1 If your child received hypothermia therapy for hypoxic ischemic encephalopathy (HIE), and you suspect that your baby’s injuries were caused by a medical staffer’s negligence, you may be able to seek help from the medical malpractice professionals at Reiter & Walsh ABC Law Centers.  If you do seek out legal counsel with us, know that your case evaluation is always free, and you will not be charged out-of-pocket for any of our legal services (for further information, please see here). We seek to help improve the people’s access to the court system and help them secure the care, therapy and support they need to ensure their child’s future. Feel free to reach out to us by phone (888-419-2229), live chat, or via email.


While we make every attempt to ensure that the information contained on this page is accurate and up-to-date, we cannot guarantee that the information on this page is current, complete, correct or accurate. Medical science is a rapidly changing field, and, as our understanding of the cellular mechanisms behind brain injury changes, current information may change drastically. We make no warranty, expressed or implied, about the accuracy or reliability of the information on this page or at any other website to which this page is linked. We periodically change, add, or update the material on this website without notice.

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