Hypoxic Ischemic Encephalopathy

A selection of articles about HIE and cooling, and potentially other issues.

  • Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005, 365(9460): 663-670.

The first of the hypothermia trials and the first evidence that there might be a therapy to improve outcomes after HIE. This was the selective head cooling trial, organized in New Zealand, but with international collaboration. 234 babies were randomized, no overall difference in terms of survival without severe disability, but the less severely affected baby subgroup did have a  benefit.

Shortly afterward, this trial from the NICHD network appeared, there were 208 babies randomized, with a reduction in the outcome of death or moderate to severe disability. Which was the case even among the more severely affected subgroup.

The next of the large multicenter trials to report from the UK, randomized 325 babies, survival was no different between groups, but there was less cerebral palsy and less developmental delay at 2 years.

By now the data were pretty convincing, especially if we add the earlier pilot trials to the mix, and a safety study by Eicher. I think other studies that were underway should have been involved in a joint review of these published data and accumulating data from those other studies (by the DSMCs) which I am sure would have demonstrated that there was solid proof of efficacy and safety. Unfortunately the trials continued for some more years, continuing to randomize infants to control arms.

  • Shankaran S, Laptook AR, Pappas A, et al.: Effect of depth and duration of cooling on deaths in the nicu among neonates with hypoxic ischemic encephalopathy: A randomized clinical trial. JAMA 2014, 312(24):2629-2639.

This trial, in contrast is what was needed next, and randomized evaluation of whether cooling for longer, or to lower temperatures was more effective. It was not. 364 babies were randomized to one of 4 combinations, looking at 33.5 degrees compared to 32 degrees, and 72 hours compared to 120 hours. Mortality was slightly (but not significantly) higher in the longer cooling group, and no advantage was seen. I don’t believe that the long term follow up has yet been published.

This was a randomized trial in 100 newborns being transported for hypothermia treatment in a tertiary center. Hypothermia was, of course, started before the transport, and was performed either with simple passive methods, or with a servo-controlled device. The device was much quicker at achieving target temperature, and the temperatures were more stable also.