Therapeutic hypothermia translates from ancient history in to practice

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Pediatric Research
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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


  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.


  1. Lee AC, Kozuki N, Blencowe H, et al. Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990. Pediatr Res 2013;74 (Suppl 1):5072.
  2. Floyer J. An essay to restore the dipping of infants in their baptism; with a dialogue betwixt a curate and a practitioner, concerning the manner of immersion. Holland, London, 1722: 1–79.
  3. Celcus AC. On Medicine, Books 1–4. Harvard University Press, Loeb Classical Library, Cambridge, MA. 1–100 AD: 1512.
  4. Hippocrates De Vetere Medicina. Harvard University Press, Loeb Classical Library, Cambridge, MA 460–375 BC: 1432.
  5. Edwards WF. On the Influence of Physical Agents on Life. Philadelphia, Haswell: Barrington and Haswell, London, 1832: 1489.
  6. Bernard C. Leçons sur la Chaleur Animale. J. B. Baillière, Paris, 1876: 1471.
  7. Miller JA Jr. Effects of variations in body temperature upon resistance to asphyxia in the neonatal guinea pig. Cold Spring Harb Symp Quant Biol 1954;19:1524.
  8. Brewin EG. Physiology of hypothermia. Int Anesthesiol Clin 1964;2:80327.
  9. Nurse S, Corbett D. Direct measurement of brain temperature during and after intraischemic hypothermia: correlation with behavioral, physiological, and histological endpoints. J Neurosci 1994;14:772634.
  10. Westin B, Miller JA Jr, Nyberg R, Wedenberg E. Neonatal asphyxia pallida treated with hypothermia alone or with hypothermia and transfusion of oxygenated blood. Surgery 1959;45:86879.
  11. Miller JA Jr, Miller FS. Mechanisms of hypothermic protection against anoxia. Adv Exp Med Biol 1972;33:57186.
  12. Duhn R, Schoen EJ, Siu M. Subcutaneous fat necrosis with extensive calcification after hypothermia in two newborn infants. Pediatrics 1968;41:6614.
  13. Silverman WA, Fertig JW, Berger AP. The influence of the thermal environment upon the survival of newly born premature infants. Pediatrics 1958;22:87686.
  14. Dunn JM, Miller JA Jr. Hypothermia combined with positive pressure ventilation in resuscitation of the asphyxiated neonate. Clinical observations in 28 infants. Am J Obstet Gynecol 1969;104:5867.
  15. Buetow KC, Klein SW. Effect of maintenance of “normal” skin temperature on survival of infants of low birth weight. Pediatrics 1964;34:16370.
  16. Day RL, Caliguiri L, Kamenski C, Ehrlich F. Body Temperature and survival of premature infants. Pediatrics 1964;34:17181.
  17. Wassink G, Gunn ER, Drury PP, Bennet L, Gunn AJ. The mechanisms and treatment of asphyxial encephalopathy. Front Neurosci 2014;8:40.
  18. Azzopardi D, Wyatt JS, Cady EB, et al. Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res 1989;25:44551.
  19. Iwata O, Iwata S, Bainbridge A, et al. Supra- and sub-baseline phosphocreatine recovery in developing brain after transient hypoxia-ischaemia: relation to baseline energetics, insult severity and outcome. Brain 2008;131(Pt 8):22206.
  20. Jensen EC, Bennet L, Hunter CJ, Power GC, Gunn AJ. Post-hypoxic hypoperfusion is associated with suppression of cerebral metabolism and increased tissue oxygenation in near-term fetal sheep. J Physiol 2006;572(Pt 1):1319.
  21. Laptook AR, Corbett RJ, Sterett R, Burns DK, Garcia D, Tollefsbol G. Modest hypothermia provides partial neuroprotection when used for immediate resuscitation after brain ischemia. Pediatr Res 1997;42:1723.
  22. Laptook AR, Corbett RJ, Burns DK, Sterett R. A limited interval of delayed modest hypothermia for ischemic brain resuscitation is not beneficial in neonatal swine. Pediatr Res 1999;46:3839.
  23. Thoresen M, Penrice J, Lorek A, et al. Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res 1995;37:66770.
  24. Sirimanne ES, Blumberg RM, Bossano D, et al. The effect of prolonged modification of cerebral temperature on outcome after hypoxic-ischemic brain injury in the infant rat. Pediatr Res 1996;39(4 Pt 1):5917.
  25. Bona E, Hagberg H, Løberg EM, Bågenholm R, Thoresen M. Protective effects of moderate hypothermia after neonatal hypoxia-ischemia: short- and long-term outcome. Pediatr Res 1998;43:73845.
  26. Alonso-Alconada D, Broad KD, Bainbridge A, et al. Brain cell death is reduced with cooling by 3.5°C to 5°C but increased with cooling by 8.5°C in a piglet asphyxia model. Stroke 2015;46:2758.
  27. Tooley JR, Satas S, Porter H, Silver IA, Thoresen M. Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective. Ann Neurol 2003;53:6572.
  28. Colbourne F, Corbett D. Delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil. Brain Res 1994;654:26572.
  29. Colbourne F, Sutherland G, Corbett D. Postischemic hypothermia. A critical appraisal with implications for clinical treatment. Mol Neurobiol 1997;14:171201.
  30. Wood T, Osredkar D, Puchades M, et al. Treatment temperature and insult severity influence the neuroprotective effects of therapeutic hypothermia. Sci Rep 2016;6:23430.
  31. Beilharz EJ, Williams CE, Dragunow M, Sirimanne ES, Gluckman PD. Mechanisms of delayed cell death following hypoxic-ischemic injury in the immature rat: evidence for apoptosis during selective neuronal loss. Brain Res Mol Brain Res 1995;29:114.
  32. Samejima K, Toné S, Kottke TJ, et al. Transition from caspase-dependent to caspase-independent mechanisms at the onset of apoptotic execution. J Cell Biol 1998;143:22539.
  33. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 1997;99:24856.
  34. Gunn AJ, Gunn TR, Gunning MI, Williams CE, Gluckman PD. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics 1998;102:1098106.
  35. Gunn AJ, Bennet L, Gunning MI, Gluckman PD, Gunn TR. Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep. Pediatr Res 1999;46:27480.
  36. Colbourne F, Corbett D. Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection. J Neurosci 1995;15:725060.
  37. Colbourne F, Corbett D, Zhao Z, Yang J, Buchan AM. Prolonged but delayed postischemic hypothermia: a long-term outcome study in the rat middle cerebral artery occlusion model. J Cereb Blood Flow Metab 2000;20:17028.
  38. Davidson JO, Wassink G, Yuill CA, Zhang FG, Bennet L, Gunn AJ. How long is too long for cerebral cooling after ischemia in fetal sheep? J Cereb Blood Flow Metab 2015;35:7518.
  39. Davidson JO, Yuill CA, Zhang FG, Wassink G, Bennet L, Gunn AJ. Extending the duration of hypothermia does not further improve white matter protection after ischemia in term-equivalent fetal sheep. Sci Rep 2016;6:25178.
  40. Shankaran S, Laptook AR, Pappas A, et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA 2014;312:262939.
  41. Trescher WH, Ishiwa S, Johnston MV. Brief post-hypoxic-ischemic hypothermia markedly delays neonatal brain injury. Brain Dev 1997;19:32638.
  42. Baena RC, Busto R, Dietrich WD, Globus MY, Ginsberg MD. Hyperthermia delayed by 24 hours aggravates neuronal damage in rat hippocampus following global ischemia. Neurology 1997;48:76873.
  43. Coimbra C, Drake M, Boris-Möller F, Wieloch T. Long-lasting neuroprotective effect of postischemic hypothermia and treatment with an anti-inflammatory/antipyretic drug. Evidence for chronic encephalopathic processes following ischemia. Stroke 1996;27:157885.
  44. Colbourne F, Auer RN, Sutherland GR. Characterization of postischemic behavioral deficits in gerbils with and without hypothermic neuroprotection. Brain Res 1998;803:6978.
  45. Schubert A. Side effects of mild hypothermia. J Neurosurg Anesthesiol 1995;7:13947.
  46. Kerenyi A, Kelen D, Faulkner SD, et al. Systemic effects of whole-body cooling to 35°C, 33.5°C, and 30°C in a piglet model of perinatal asphyxia: implications for therapeutic hypothermia. Pediatr Res 2012;71:57382.
  47. Weinrauch V, Safar P, Tisherman S, Kuboyama K, Radovsky A. Beneficial effect of mild hypothermia and detrimental effect of deep hypothermia after cardiac arrest in dogs. Stroke 1992;23:145462.
  48. Simbruner G, Nanz S, Fleischhacker E, Derganc M. Brain temperature discriminates between neonates with damaged, hypoperfused, and normal brains. Am J Perinatol 1994;11:13743.
  49. Battin MR, Penrice J, Gunn TR, Gunn AJ. Treatment of term infants with head cooling and mild systemic hypothermia (35.0°C and 34.5°C) after perinatal asphyxia. Pediatrics 2003;111:24451.
  50. Tooley J, Satas S, Eagle R, Silver IA, Thoresen M. Significant selective head cooling can be maintained long-term after global hypoxia ischemia in newborn piglets. Pediatrics 2002;109:6439.
  51. Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics 1998;102(4 Pt 1):88592.
  52. Laptook AR, Shalak L, Corbett RJ. Differences in brain temperature and cerebral blood flow during selective head versus whole-body cooling. Pediatrics 2001;108:110310.
  53. Thoresen M, Satas S, Puka-Sundvall M, et al. Post-hypoxic hypothermia reduces cerebrocortical release of NO and excitotoxins. Neuroreport 1997;8:335962.
  54. Nakashima K, Todd MM, Warner DS. The relation between cerebral metabolic rate and ischemic depolarization. A comparison of the effects of hypothermia, pentobarbital, and isoflurane. Anesthesiology 1995;82:1199208.
  55. Bart RD, Takaoka S, Pearlstein RD, Dexter F, Warner DS. Interactions between hypothermia and the latency to ischemic depolarization: implications for neuroprotection. Anesthesiology 1998;88:126673.
  56. Tan WK, Williams CE, During MJ, et al. Accumulation of cytotoxins during the development of seizures and edema after hypoxic-ischemic injury in late gestation fetal sheep. Pediatr Res 1996;39:7917.
  57. Jensen FE, Wang C, Stafstrom CE, Liu Z, Geary C, Stevens MC. Acute and chronic increases in excitability in rat hippocampal slices after perinatal hypoxia in vivo. J Neurophysiol 1998;79:7381.
  58. Bennet L, Roelfsema V, George S, Dean JM, Emerald BS, Gunn AJ. The effect of cerebral hypothermia on white and grey matter injury induced by severe hypoxia in preterm fetal sheep. J Physiol 2007;578(Pt 2):491506.
  59. Bennet L, Dean JM, Wassink G, Gunn AJ. Differential effects of hypothermia on early and late epileptiform events after severe hypoxia in preterm fetal sheep. J Neurophysiol 2007;97:5728.
  60. Dean JM, George SA, Wassink G, Gunn AJ, Bennet L. Suppression of post-hypoxic-ischemic EEG transients with dizocilpine is associated with partial striatal protection in the preterm fetal sheep. Neuropharmacol 2006;50:491503.
  61. George SA, Barrett RD, Bennet L, Mathai S, Jensen EC, Gunn AJ. Nonadditive neuroprotection with early glutamate receptor blockade and delayed hypothermia after asphyxia in preterm fetal sheep. Stroke 2012;43:31147.
  62. Mallard C, Davidson JO, Tan S, et al. Astrocytes and microglia in acute cerebral injury underlying cerebral palsy associated with preterm birth. Pediatr Res 2014;75:23440.
  63. Roelfsema V, Bennet L, George S, et al. Window of opportunity of cerebral hypothermia for postischemic white matter injury in the near-term fetal sheep. J Cereb Blood Flow Metab 2004;24:87786.
  64. Shankaran S, Laptook A, Wright LL, et al. Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants. Pediatrics 2002;110(2 Pt 1):37785.
  65. Battin MR, Dezoete JA, Gunn TR, Gluckman PD, Gunn AJ. Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia. Pediatrics 2001;107:4804.
  66. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013;1:CD003311.
  67. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005;365:66370.
  68. Shankaran S, Laptook AR, Ehrenkranz RA, et al.; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:157484.
  69. Azzopardi DV, Strohm B, Edwards AD, et al.; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009;361:134958.
  70. Simbruner G, Mittal RA, Rohlmann F, MucheR. Trial Participants. Systemic hypothermia after neonatal encephalopathy: outcomes of RCT. Pediatrics 2010;126:e7718.
  71. Zhou WH, Cheng GQ, Shao XM, et al. China Study Group. Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China. J Pediatr 2010;157:36772, 372.e1–3.
  72. Jacobs SE, Morley CJ, Inder TE, et al.; Infant Cooling Evaluation Collaboration. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med 2011;165:692700.
  73. Thoresen M, Hellström-Westas L, Liu X, de Vries LS. Effect of hypothermia on amplitude-integrated electroencephalogram in infants with asphyxia. Pediatrics 2010;126:e1319.
  74. Gunn AJ, Wyatt JS, Whitelaw A, et al.; CoolCap Study Group. Therapeutic hypothermia changes the prognostic value of clinical evaluation of neonatal encephalopathy. J Pediatr 2008;152:558, 58.e1.
  75. Azzopardi D, Strohm B, Marlow N, et al.; TOBY Study Group. Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med 2014;371:1409.
  76. Shankaran S, Pappas A, McDonald SA, et al.; Eunice Kennedy Shriver NICHD Neonatal Research Network. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 2012;366:208592.
  77. Thoresen M, Whitelaw A. Cardiovascular changes during mild therapeutic hypothermia and rewarming in infants with hypoxic-ischemic encephalopathy. Pediatrics 2000;106(1 Pt 1):929.
  78. Gordon CJ, Heath JE. Integration and central processing in temperature regulation. Annu Rev Physiol 1986;48:595612.
  79. Gunn TR, Wilson NJ, Aftimos S, Gunn AJ. Brain hypothermia and QT interval. Pediatrics 1999;103(5 Pt 1):1079.
  80. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:55763.
  81. Todd MM, Hindman BJ, Clarke WR, Torner JC; Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) Investigators. Mild intraoperative hypothermia during surgery for intracranial aneurysm. N Engl J Med 2005;352:13545.

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Author information


  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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