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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\u2010optimal. 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\u2010excitotoxic, anti\u2010apoptotic, and anti\u2010inflammatory 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.<\/jats:p>","DOI":"10.1111\/dmcn.14610","type":"journal-article","created":{"date-parts":[[2020,7,2]],"date-time":"2020-07-02T10:49:45Z","timestamp":1593686985000},"page":"1131-1137","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Combination treatments with therapeutic hypothermia for hypoxic\u2010ischemic neuroprotection"],"prefix":"10.1111","volume":"62","author":[{"given":"Kelly Q","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Physiology The University of Auckland Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne O","family":"Davidson","sequence":"additional","affiliation":[{"name":"Department of Physiology The University of Auckland Auckland New 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