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It is now over 25 years since publication of the first experimental study demonstrating that mild hypothermia after transient hypoxia-ischaemia ameliorates delayed energy failure in a newborn piglet model.1 Since then, and following several large randomised controlled trials, therapeutic hypothermia (TH) has become, and currently remains the only, treatment shown to reduce death and disability in infants born following perinatal hypoxia-ischaemia. In the early experimental studies, cooling was initiated immediately after the insult; subsequent studies have shown that delayed initiation of cooling results in a significant reduction in the therapeutic effect of cooling.2 The Total Body Hypothermia (TOBY) trial showed a trend to improved outcome in infants cooled within 4 hours of delivery and it has been shown that motor outcomes improved in infants who were cooled within 3 hours of delivery compared with those cooled after 3 hours of delivery.3 Conversely, there is limited evidence regarding the efficacy of cooling started beyond 12 hours of age. Therefore, current evidence would suggest that the sooner cooling is commenced, the more likely it is to be beneficial.
Translating experimental science into clinical practice is immensely challenging. In designing the first clinical trials of TH, investigators had to take a pragmatic view on when to start cooling infants, allowing enough time for eligible infants to be identified and enrolled into the studies. It is to the investigators’ credit that the three largest trials (CooCap, NICHD and TOBY trials) all used similar entry criteria (mild-to-moderate hypoxic-ischaemic encephalopathy (HIE)), depth of cooling (33.5°C), time of commencement of cooling …
Contributors TA wrote the initial manuscript draft and EC subsequently revised it with both authors agreeing on the final submitted draft.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.