Combination treatments with therapeutic hypothermia for hypoxic‐ischemic neuroprotection

Abstract

Therapeutic hypothermia is now proven to reduce death or disability in term and near‐term born infants with moderate to severe hypoxic‐ischemic encephalopathy. Nevertheless, many infants still survive with disability, despite treatment with hypothermia. Recent preclinical and clinical studies suggest that current protocols for therapeutic hypothermia are near‐optimal. The obvious strategy, in addition to improving early initiation of therapeutic hypothermia after birth, is to combine hypothermia with other neuroprotective agents. We review evidence that the mechanisms of action of many promising agents overlap with the anti‐excitotoxic, anti‐apoptotic, and anti‐inflammatory mechanisms of hypothermia, leading to a lack of benefit from combination treatment. Moreover, even apparently beneficial combinations have failed to translate in clinical trials. These considerations highlight the need for preclinical studies to test clinically realistic protocols of timing and duration of treatment, before committing to large randomized controlled trials.

A combination of phenobarbital and the bumetanide derivative bumepamine prevents neonatal seizures and subsequent hippocampal neurodegeneration in a rat model of birth asphyxia

“…17,18,41 Currently, therapeutic hypothermia is the only clinically established treatment for neuroprotection following asphyxia in term neonates; however, about half of survivors exhibit brain damage and persistent neurodevelopmental disabilities despite receiving hypothermia. 42 Thus one obvious strategy is to combine hypothermia with other neuroprotective agents. 42,43 The combination of bumepamine and phenobarbital described here is an interesting option because it combines strong antiseizure efficacy with neuroprotective activity.…”

“…42 Thus one obvious strategy is to combine hypothermia with other neuroprotective agents. 42,43 The combination of bumepamine and phenobarbital described here is an interesting option because it combines strong antiseizure efficacy with neuroprotective activity. Phenobarbital alone does not improve the neuroprotective efficacy of therapeutic hypothermia in infants.…”

“…Currently, therapeutic hypothermia is the only clinically established treatment for neuroprotection following asphyxia in term neonates; however, about half of survivors exhibit brain damage and persistent neurodevelopmental disabilities despite receiving hypothermia 42 . Thus one obvious strategy is to combine hypothermia with other neuroprotective agents 42,43 .…”

The Function of the NMDA Receptor in Hypoxic-Ischemic Encephalopathy

“…Drugs such as melatonin, edaravone, erythropoietin (EPO), and growth factor have also been used for the treatment of hypoxic ischemic injury (Hua et al, 2017;Zhou et al, 2020). Melatonin has antioxidant, anti-inflammatory, and antiapoptotic effects (Alonso-Alconada et al, 2013).…”

The Effect of the Excretion of Calcium, Magnesium, and Phosphate on the Serum Levels of These Substances in Newborns Who Therapeutic Hypothermia for Hypoxic Ischemic Encephalopathy

“…Therapeutic hypothermia (TH) is a treatment method proven to reduce mortality and morbidity in full-term and near-term babies with moderate and severe HIE [4].…”