Elsevier

The Journal of Pediatrics

Volume 159, Issue 5, November 2011, Pages 851-858.e1
The Journal of Pediatrics

Commentary
Hypothermia and Other Treatment Options for Neonatal Encephalopathy: An Executive Summary of the Eunice Kennedy Shriver NICHD Workshop

https://doi.org/10.1016/j.jpeds.2011.08.004Get rights and content

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Pathophysiological Basis for Therapeutic Strategies

Our current therapeutic approach to treating neonatal encephalopathy is based on understanding the evolution of neuronal damage after hypoxic ischemic injury.9, 10, 11 The pathway of cerebral injury in term infants with HIE is not always clear. Many factors, including etiology, extent of hypoxia or ischemia, maturational stage of the brain, regional cerebral blood flow, and general health before the injury, can affect the pattern and extent of brain injury, as well as the outcome after injury.11

Clinical Trials of Hypothermic Neural Rescue

Clinical trials of hypothermic neural rescue have shown remarkably similar results using a core temperature of 33.5-34.5°C for 72 hours, starting within 6 hours of birth. Although some trials have used preferential head cooling, whereas others have used whole-body cooling, all trials controlled the therapy using temperature monitoring. In all trials, both the degree of cooling and core temperature were monitored continuously.

The CoolCap,1 NICHD,2 TOBY,3 neo.nEURO.network,4 China Study Group,5

Further Research into Hypothermic Neural Rescue

Despite the strong evidence of benefits from multiple large, well-controlled studies, many gaps in knowledge remain. Cooling was intended as a treatment for HIE, but neonatal encephalopathy may have diverse etiologies (besides hypoxia and ischemia) despite a consistent clinical presentation. In infants with recognized HIE, the precise timing, nature, and severity of the hypoxic-ischemic insult is seldom certain. The infant’s maturity, nutritional and hormonal status, inflammatory, and

Clinical Trials of Adjuvant Therapies

Data from animal models of asphyxia suggest that neurologic outcome after HIE can be improved by adding adjuvant therapies to hypothermia, beginning in the hours to days after the insult. Thus, a high priority is the development of sufficient experimental knowledge to warrant assessment of these promising neuroprotective agents in clinical trials. Phase 1-2 studies using biomarker outcomes and involving small numbers of infants are essential to assess safety and potential efficacy before new

Biomarkers

Biomarkers have been essential to research in HIE.70 The original finding of delayed brain injury in the human infant after an asphyxial event was discovered using phosphorus magnetic resonance spectroscopy (MRS).71 This technique was subsequently used as the prototypical bridging biomarker of HIE to evaluate the therapeutic effect of hypothermia in early animal studies.72 Phosphorus MRS is cumbersome and not widely available; however, MRS biomarkers, such as proton spectroscopy and diffusion

Implementation Issues for HIE Therapy

The workshop participants suggested a framework for hospitals as well as practicing clinicians in which therapeutic hypothermia is available. Therapeutic hypothermia can be offered for infants who meet the criteria of published trials provided that the infrastructure and trained personnel to perform hypothermia are in place.28, 29, 30 Eligibility criteria include a pH of ≤7.0 or a base deficit of ≥16 mmol/L in a sample of umbilical cord blood or any blood obtained during the first hour after

Registries

The establishment of several registries allows monitoring of implementation, detection of rare adverse events, and the opportunity to learn from variation in practice. Currently, the Vermont Oxford Network has an encephalopathy registry,44 and a TOBY registry is in place.43 Registries ideally should include all infants treated with hypothermia regardless of gestational age and collect information on variations and confounders, including duration of cooling, timing of initiation of cooling,

Summary

HIE is not a single disease with a single cause, but rather is characterized by great diversity in the timing and magnitude of brain injury. Thus, it is unreasonable to expect any single intervention to provide uniformly favorable outcomes. The known heterogeneity in neuropathological changes after perinatal HIE, combined with the potential regional heterogeneity of treatment effects, will lead to marked differences in outcomes among survivors of HIE (eg, physical disability vs cognitive

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      Although over half of infants with HIE present within a mild spectrum, past clinical trials have focused exclusively on moderately and severely affected infants.3–7 This was understandable initially at that time when the safety profile of interventions was largely unknown.8,9 The establishment of hypothermia for moderate and severe HIE leads to a decrease of death and disability at 2 years from 45% to 29% as recently demonstrated in contemporary studies.10,11

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    The Workshop was supported by the National Institutes of Health Office of Rare Diseases. R.G. receives financial support from Olympic Medical/Natus for follow-up of the Cool Cap cohort of infants. The other authors declare no conflicts of interest.

    A list of Eunice Kennedy Shriver National Institute of Child Health and Human Development Hypothermia Workshop speakers and moderators is available at www.jpeds.com (Appendix).

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