Discussion
death, hypothermia, hypoxia, hypoxic injury, brain injury, HIE, cerebral palsy, MR, disability
HYPOXIA, SECONDARY, CEREBRAL PALSY
This nested cohort study involved a subgroup analysis of data from the HELIX trial, which was, to our knowledge, the largest clinical trial of hypothermia reported to date and the first to use quantitative MR biomarkers in a multicountry setting using harmonized cross-platform sequences. Findings revealed that whole-body hypothermia was not associated with reductions in brain injury measured by thalamic NAA levels, thalamic lactate to NAA or NAA to creatinine PARs, tract-based spatial statistics of whole-brain white matter FA, or conventional MR imaging injury scores, irrespective of place of birth. The direction of treatment effect (or lack of treatment effect) measured using thalamic NAA levels, thalamic lactate to NAA PARs, and NAA to creatinine PARs was associated with the clinical outcomes. Whole-body hypothermia was not associated with reductions in death or disability at 18 to 22 months among both inborn and outborn neonates. Because the HELIX trial was adequately powered to assess the clinical outcomes, these data provide the first validation, to our knowledge, of MR spectroscopic biomarkers as a surrogate end point in HIE neuroprotection trials.Although earlier clinical trials of whole-body hypothermia have reported MR imaging data obtained as part of standard clinical care,The first Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) hypothermia trialAn inverse association was seen between mortality and cerebral palsy at 18 to 22 months. For every 10 neonates treated with whole-body hypothermia, at least 1 additional neonate died and 1 case of cerebral palsy was averted. Therefore, it is important that the primary outcome of any neuroprotective intervention for HIE, particularly in NICUs in LMICs, remains the composite of death or moderate or severe disability, and reduction in cerebral palsy should always be considered in the context of shifts in mortality within the same trial and not in isolation.Although many observational studies from LMICs primarily recruiting neonates with mild brain injuryIt is unlikely that the lack of hypothermic neuroprotection seen in the HELIX trialSecond, the HELIX trial results did not change when the 10 neonates born at home were excluded. While the inclusion criteria of the HELIX trial (which required resuscitation at birth) were less stringent than those of the NICHD NRN trialOne possible explanation for the lack of hypothermic neuroprotection is difference in the nature and timing of intrapartum hypoxia. In preclinical models, hypothermia was associated with the prevention of secondary energy failure only when the hypoxic injury was single, acute, and occurred in a previously healthy animal