Treatment for HIE: Combining Xenon with Neonatal Cooling

Hypothermia therapy, or brain cooling, is the standard treatment for hypoxic-ischemic encephalopathy (HIE). It can reduce the extent of permanent brain damage if given very shortly after birth or the oxygen-depriving incident (within six hours, though there may be some benefit from the therapy up to 24 hours). Using a cooling cap or blanket, the baby’s body temperature is lowered to 33.5 degrees Celsius for 72 hours. Brain cells are able to recover during this period of cooling, lessening or preventing the severity, permanence, and spread of brain damage.

Despite the benefits of cooling, 40-50% of babies with moderate to severe HIE will still have poor developmental outcomes after hypothermia therapy. This is because therapeutic hypothermia has a reduced effect following severe asphyxial brain injury. To help these babies, researchers are experimenting with different improved treatment options that can be implemented alongside therapeutic hypothermia (1).

Xenon as a Combinatory Agent

Treating HIE - Combining Xenon with Brain Cooling The use of xenon as a combinatory agent to the cooling process has shown improved outcomes. Xenon is a noble gas that has been used as a safe anesthetic since 1951. It causes reduction in neurotransmitter release, which is a significant part of the neurotoxic cascade of cell death that occurs in neonatal HIE (2).

Studies have proven that combining hypothermia therapy with xenon reduced neonatal injury more effectively than any other combination of hypothermia therapy and other anesthetics called NMDA glutamate receptor antagonists. The combination of hypothermia therapy and xenon has been found to double neuroprotection after moderate HIE when inhaled at a sub-anesthetic dosage of 50% for an 18 hour period during the 72 hours of hypothermia therapy. It also stabilizes cerebrovascular reactivity and blood pressure (1).

Combining Xenon with Hypothermia Therapy

In one study, which included data from March 2010 to April 2011, 14 infants were given 72 hours of cooling within 2-10 hours of birth. In combination with the cooling, the infants inhaled 50% xenon for up to 18 hours. There was a reported depression of seizure activity while the xenon was being inhaled. Furthermore, the infants returned for evaluation at 18-20 months and were noted to be developing normally or experiencing only mild delays.

Future Use of Xenon in Treating Babies with HIE

According to these studies, however, xenon is still not predicted to be used in most hypothermia cooling procedures because:

  • Xenon is expensive and hard to come by (it is a trace element manufactured by fractional distillation of liquefied air during oxygen purification).
  • Xenon requires a special closed circuit system to be used properly, which is expensive and not widely available.
  • The quantity of xenon used must be studied more closely (70% and higher xenon concentrations can cause respiratory depression).
  • The results of many studies are inconclusive regarding xenon’s benefits for infants with severe cases of HIE (2).

The use of xenon inhalation during hypothermia therapy has had benefits for infants with mild to severe HIE, but has not shown marked improvement in infants with the most severe cases. Implementing its use would require further studies regarding the ideal quantity used, the ideal time to incorporate it in the cooling process, and which babies benefit more from its use.


  1. Sabir, H., Osredkar, D., Maes, E., Wood, T., & Thoresen, M. (2016). Xenon Combined with Therapeutic Hypothermia Is Not Neuroprotective after Severe Hypoxia-Ischemia in Neonatal Rats. Plos One,11(6). doi:10.1371/journal.pone.0156759
  2. Amer, A. R., & Oorschot, D. E. (2018). Xenon Combined With Hypothermia in Perinatal Hypoxic-Ischemic Encephalopathy: A Noble Gas, a Noble Mission. Pediatric Neurology,84, 5-10. doi:10.1016/j.pediatrneurol.2018.02.009
  3. Azzopardi, D., Robertson, N. J., Bainbridge, A., Cady, E., Charles-Edwards, G., Deierl, A., . . . Edwards, A. D. (2016). Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): A proof-of-concept, open-label, randomised controlled trial. The Lancet Neurology,15(2), 145-153. doi:10.1016/s1474-4422(15)00347-6
  4. Xenon Ventilation During Therapeutic Hypothermia in Neonatal Encephalopathy: A Feasibility Study. (2014). Pediatrics,133(5). doi:10.1542/peds.2013-0787d

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