Therapeutic hypothermia translates from ancient history in to practice

Journal name:
Pediatric Research
(2017)
Volume:
81,
Pages:
202–209
DOI:
doi:10.1038/pr.2016.198
Received
Accepted
Accepted article preview online
Advance online publication

Abstract

Acute postasphyxial encephalopathy around the time of birth remains a major cause of death and disability. The possibility that hypothermia may be able to prevent or lessen asphyxial brain injury is a “dream revisited”. In this review, a historical perspective is provided from the first reported use of therapeutic hypothermia for brain injuries in antiquity, to the present day. The first uncontrolled trials of cooling for resuscitation were reported more than 50 y ago. The seminal insight that led to the modern revival of studies of neuroprotection was that after profound asphyxia, many brain cells show initial recovery from the insult during a short “latent” phase, typically lasting ~6h, only to die hours to days later during a “secondary” deterioration phase characterized by seizures, cytotoxic edema, and progressive failure of cerebral oxidative metabolism. Studies designed around this conceptual framework showed that mild hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration to allow the secondary deterioration to resolve, is associated with potent, long-lasting neuroprotection. There is now compelling evidence from randomized controlled trials that mild induced hypothermia significantly improves intact survival and neurodevelopmental outcomes to midchildhood.

At a glance

Figures

  1. Figure 1:

    Schematic diagram showing the phases of primary and secondary energy failure after hypoxia-ischemia on magnetic resonance spectroscopy (MRS), and the amelioration of secondary energy failure with therapeutic hypothermia started during the latent phase after transient hypoxia-ischemia in a newborn piglet. Upper panel shows phosphorus-31 MRS NTP/EPP peak area ratio at baseline, during and after hypoxia-ischemia. The preservation of high energy phosphates with hypothermia vs. normothermia is shown on the diagram (blue line vs. red line) and in the representative spectra at 48h (red normothermia and blue hypothermia). Lower panel shows proton MRS lactate/NAA peak area ratio at baseline, and during and after hypoxia-ischemia. The amelioration of the rise in lactate/NAA with hypothermia vs. normothermia is shown on the diagram (blue line vs. red line) and in the representative spectra at 48h (red normothermia and blue hypothermia). EPP: exchangeable phosphate pool; NTP: nucleotide tri-phosphate; NAA: N-acetyl aspartate.

  2. Figure 2:

    The effect of hypothermia started 3h after a 30min period of cerebral ischemia in term-equivalent fetal sheep (38). The period of ischemia is shown by the dashed arrow. Cooling is shown by the filled blue bar. The top panel shows changes in extradural temperature (°C) after sham ischemia (open circles), ischemia-normothermia (solid black circles) and ischemia-hypothermia (inverted blue triangles). The lower three panels show changes in cortical impedance (%) a measure of changes in cell swelling (cytotoxic edema), change in electroencephalographic (EEG) power (dB, decibels) and change in the spectral edge frequency of the EEG (SEF, Hz). The hypothermia group shows complete suppression of the secondary rise in impedance, greater recovery of EEG power after resolution of delayed seizures (which occur from ~9–72h) and improved SEF that persists after rewarming. Data are mean ± SEM.

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Affiliations

  1. Department of Physiology, School of Medical Sciences, University of Auckland, Auckland, New Zealand

    • Alistair J. Gunn,
    • Guido Wassink &
    • Laura Bennet
  2. Department of Neonatology, Warren Alpert Medical School, Brown University, Women & Infants Hospital, Providence, Rhode Island

    • Abbot R. Laptook
  3. Institute for Women’s Health, University College London, London, UK

    • Nicola J. Robertson
  4. Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan

    • John D. Barks
  5. Neonatal Neuroscience, School of Clinical Sciences, University of Bristol, Bristol, UK

    • Marianne Thoresen
  6. Department of Physiology, University of Oslo, Oslo, Norway

    • Marianne Thoresen

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