Introduction and objective:
Hypoxic-ischemic encephalopathy is one of the main types of neonatal encephalopathy in which perinatal asphyxia has been proven. The incidence of neonatal hypoxic-ischemic encephalopathy is estimated at 1–8 per 1,000 newborns and is associated with a variety of long-term complications. The study presents standard and novel treatment pathways and their limitations.

Review methods:
A literature search was performed in the PubMed and Google Scholar databases using the following phrases ‘hypoxic-ischemic encephalopathy’, ‘therapeutic hypothermia’, and ‘novel treatment’. The research studies used in the review were published between 2019 – 2025.

Brief description of the state of knowledge:
A thorough understanding of the pathogenesis of hypoxic-ischemic encephalopathy and neuroplastic features of the neonatal brain has allowed for the singling-out of therapeutic hypothermia as a standard procedure making it possible to significantly reduce mortality and improve the quality of life. However, the condition affects low-income countries even more frequently and, despite treatment, there is a 22% of severe complications or death. Current research focuses on new treatments options like therapeutic hypothermia modifications, such as selective head cooling, whole-body cooling, as well as pharmacotherapy with erythropoietin, stem cells, allopurinol, caffeine, melatonin, endocannabinoids, colony stimulating factors, metformin and more.

Summary:
Numerous limitations of therapeutic hypothermia necessitate further investigation. Another promising strategy may be a modification of therapeutic hypothermia and combination therapy.