Abstract
Purpose of Review
Therapeutic hypothermia reduces death or disability in term and near-term infants with moderate-severe hypoxic-ischemic encephalopathy. Nevertheless, many infants still survive with disability, despite hypothermia, supporting further research in to ways to further improve neurologic outcomes.
Recent Findings
Recent clinical and experimental studies have refined our understanding of the key parameters for hypothermic neuroprotection, including timing of initiation, depth, and duration of hypothermia, and subsequent rewarming rate. However, important knowledge gaps remain. There is encouraging clinical evidence from a small phase II trial that combined treatment of hypothermia with recombinant erythropoietin further reduces risk of disability but definitive studies are still needed.
Summary
In conclusion, recent studies suggest that current protocols for therapeutic hypothermia are near-optimal, and that the key to better neurodevelopmental outcomes is earlier diagnosis and initiation of hypothermia after birth. Further research is essential to find and evaluate ways to further improve outcomes after hypoxic-ischemic encephalopathy, including add-on therapies for therapeutic hypothermia and preventing pyrexia during labor and delivery.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Lee AC, Kozuki N, Blencowe H, Vos T, Bahalim A, Darmstadt GL, 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):50–72.
Vannucci RC. Hypoxic-ischemic encephalopathy. Am J Perinatol. 2000;17(3):113–20.
Westgate JA, Gunn AJ, Gunn TR. Antecedents of neonatal encephalopathy with fetal acidaemia at term. Br J Obstet Gynaecol. 1999;106(8):774–82.
Cowan F, Rutherford M, Groenendaal F, Eken P, Mercuri E, Bydder GM, et al. Origin and timing of brain lesions in term infants with neonatal encephalopathy. Lancet. 2003;361(9359):736–42.
Gunn AJ, Laptook AR, Robertson NJ, Barks JD, Thoresen M, Wassink G, et al. Therapeutic hypothermia translates from ancient history in to practice. Pediatr Res. 2017;81(1–2):202–9.
Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2003;4:CD003311.
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(2):248–56.
Tan WK, Williams CE, During MJ, Mallard CE, Gunning MI, Gunn AJ, 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(5):791–7.
Azzopardi D, Wyatt JS, Cady EB, Delpy DT, Baudin J, Stewart AL, et al. Prognosis of newborn infants with hypoxic-ischemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res. 1989;25(5):445–51.
•• 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(5):751–8 Systematic study in fetal sheep showing that continuing hypothermia for 5 days instead of 3 days does not further improve outcomes and may be deleterious.
•• Davidson JO, Draghi V, Whitham S, Dhillon SK, Wassink G, Bennet L, et al. How long is sufficient for optimal neuroprotection with cerebral cooling after ischemia in fetal sheep? J Cereb Blood Flow Metab. 2018;38(6):1047–59 Systematic study in fetal sheep showing that hypothermia must be continued for 72 hours for optimal benefit.
Vannucci RC, Towfighi J, Vannucci SJ. Secondary energy failure after cerebral hypoxia-ischemia in the immature rat. J Cereb Blood Flow Metab. 2004;24(10):1090–7.
Roth SC, Baudin J, Cady E, Johal K, Townsend JP, Wyatt JS, et al. Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years. Dev Med Child Neurol. 1997;39(11):718–25.
Williams CE, Gunn AJ, Mallard C, Gluckman PD. Outcome after ischemia in the developing sheep brain: an electroencephalographic and histological study. Ann Neurol. 1992;31(1):14–21.
Lorek A, Takei Y, Cady EB, Wyatt JS, Penrice J, Edwards AD, et al. Delayed (“secondary”) cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. Pediatr Res. 1994;36(6):699–706.
Sabir H, Scull-Brown E, Liu X, Thoresen M. Immediate hypothermia is not neuroprotective after severe hypoxia-ischemia and is deleterious when delayed by 12 hours in neonatal rats. Stroke. 2012;43(12):3364–70.
Hagberg H, Mallard C, Rousset CI, Thornton C. Mitochondria: hub of injury responses in the developing brain. Lancet Neurol. 2014;13(2):217–32.
Gunn AJ, Thoresen M. Hypothermic neuroprotection. NeuroRx. 2006;3(2):154–69.
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.
Guillet R, Edwards AD, Thoresen M, Ferriero DM, Gluckman PD, Whitelaw A, et al. Seven- to eight-year follow-up of the CoolCap trial of head cooling for neonatal encephalopathy. Pediatr Res. 2012;71(2):205–9.
Azzopardi D, Strohm B, Marlow N, Brocklehurst P, Deierl A, Eddama O, et al. Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med. 2014;371(2):140–9.
Shankaran S, Pappas A, McDonald SA, Vohr BR, Hintz SR, Yolton K, et al. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med. 2012;366(22):2085–92.
Laptook AR, Shalak L, Corbett RJ. Differences in brain temperature and cerebral blood flow during selective head versus whole-body cooling. Pediatrics. 2001;108(5):1103–10.
Rutherford MA, Azzopardi D, Whitelaw A, Cowan F, Renowden S, Edwards AD, et al. Mild hypothermia and the distribution of cerebral lesions in neonates with hypoxic-ischemic encephalopathy. Pediatrics. 2005;116(4):1001–6.
Sarkar S, Donn SM, Bapuraj JR, Bhagat I, Barks JD. Distribution and severity of hypoxic-ischaemic lesions on brain MRI following therapeutic cooling: selective head versus whole body cooling. Arch Dis Child Fetal Neonatal Ed. 2012;97(5):F335–9.
Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA. Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Arch Pediatr Adolesc Med. 2012;166(6):558–66.
• Wassink G, Davidson JO, Lear CA, Juul SE, Northington F, Bennet L, et al. A working model for hypothermic neuroprotection. J Physiol. 2018. https://doi.org/10.1113/JP274928 Systematic discussion of a framework to understand neuroprotection with therapeutic hypothermia.
•• Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, Tyson JE, et al. Effect of depth and duration of cooling on death or disability at age 18 months among neonates with hypoxic-ischemic encephalopathy: a randomized clinical trial. JAMA. 2017;318(1):57–67 Very important, large randomized controlled trial showing that longer or deeper cooling does not further improve outcomes after neonatal encephalopathy.
Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574–84.
Jary S, Smit E, Liu X, Cowan FM, Thoresen M. Less severe cerebral palsy outcomes in infants treated with therapeutic hypothermia. Acta Paediatr. 2015;104(12):1241–7.
• Liu X, Jary S, Cowan F, Thoresen M. Reduced infancy and childhood epilepsy following hypothermia-treated neonatal encephalopathy. Epilepsia. 2017;58(11):1902–11 Cohort study suggesting reduced risk of epilepsy in children treated with therapeutic hypothermia for neonatal encephalopathy.
Thoresen M, Tooley J, Liu X, Jary S, Fleming P, Luyt K, et al. Time is brain: starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns. Neonatology. 2013;104(3):228–33.
Lemyre B, Ly L, Chau V, Chacko A, Barrowman N, Whyte H, et al. Initiation of passive cooling at referring Centre is most predictive of achieving early therapeutic hypothermia in asphyxiated newborns. Paediatr Child Health. 2017;22(5):264–8.
Thoresen M, Penrice J, Lorek A, Cady EB, Wylezinska M, Kirkbride V, et al. Mild hypothermia after severe transient hypoxia-ischemia ameliorates delayed cerebral energy failure in the newborn piglet. Pediatr Res. 1995;37(5):667–70.
Colbourne F, Auer RN, Sutherland GR. Characterization of postischemic behavioral deficits in gerbils with and without hypothermic neuroprotection. Brain Res. 1998;803(1–2):69–78.
• Wood T, Osredkar D, Puchades M, Maes E, Falck M, Flatebo T, et al. Treatment temperature and insult severity influence the neuroprotective effects of therapeutic hypothermia. Sci Rep. 2016;6:23430 Systematic, well controlled study in P7 rats demonstrating the adverse effects of pyrexia after hypoxia-ischemia.
Alonso-Alconada D, Broad KD, Bainbridge A, Chandrasekaran M, Faulkner SD, Kerenyi A, et al. Brain cell death is reduced with cooling by 3.5 degrees C to 5 degrees C but increased with cooling by 8.5 degrees C in a piglet asphyxia model. Stroke. 2015;46(1):275–8.
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(12):1702–8.
Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, Tyson JE, 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):2629–39.
Edwards AD, Brocklehurst P, Gunn AJ, Halliday H, Juszczak E, Levene M, et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ. 2010;340:c363.
Thoresen M, Whitelaw A. Cardiovascular changes during mild therapeutic hypothermia and rewarming in infants with hypoxic-ischaemic encephalopathy. Pediatrics. 2000;106(1):92–9.
Battin MR, Bennet L, Gunn AJ. Rebound seizures during rewarming. Pediatrics. 2004;114(5):1369.
Hashimoto T, Yonetani M, Nakamura H. Selective brain hypothermia protects against hypoxic-ischemic injury in newborn rats by reducing hydroxyl radical production. Kobe J Med Sci. 2003;49(3–4):83–91.
Nakashima K, Todd MM. Effects of hypothermia on the rate of excitatory amino acid release after ischemic depolarization. Stroke. 1996;27(5):913–8.
Wang B, Armstrong JS, Lee JH, Bhalala U, Kulikowicz E, Zhang H, et al. Rewarming from therapeutic hypothermia induces cortical neuron apoptosis in a swine model of neonatal hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab. 2015;35(5):781–93.
Wang B, Armstrong JS, Reyes M, Kulikowicz E, Lee JH, Spicer D, et al. White matter apoptosis is increased by delayed hypothermia and rewarming in a neonatal piglet model of hypoxic ischemic encephalopathy. Neuroscience. 2016;316:296–310.
Nakamura T, Miyamoto O, Yamagami S, Hayashida Y, Itano T, Nagao S. Influence of rewarming conditions after hypothermia in gerbils with transient forebrain ischemia. J Neurosurg. 1999;91(1):114–20.
Gerrits LC, Battin MR, Bennet L, Gonzalez H, Gunn AJ. Epileptiform activity during rewarming from moderate cerebral hypothermia in the near-term fetal sheep. Pediatr Res. 2005;57(3):342–6.
• Davidson JO, Wassink G, Draghi V, Dhillon SK, Bennet L, Gunn AJ. Limited benefit of slow rewarming after cerebral hypothermia for global cerebral ischemia in near-term fetal sheep. J Cereb Blood Flow Metab. 2018:271678X18791631. Controlled study in fetal sheep suggesting that duration of therapeutic hypothermia after severe hypoxia-ischemia is more important that the rate of rewarming.
• Laptook AR, Shankaran S, Tyson JE, Munoz B, Bell EF, Goldberg RN, et al. Effect of therapeutic hypothermia initiated after 6 hours of age on death or disability among newborns with hypoxic-ischemic encephalopathy: A randomized clinical trial. JAMA. 2017;318(16):1550–60 Large randomized controlled trial that suggests limited benefit if hypothermia is delayed outside of its known window of opportunity.
Morishima HO, Glaser B, Niemann WH, James LS. Increased uterine activity and fetal deterioration during maternal hyperthermia. Am J Obstet Gynecol. 1975;121(4):531–8.
Spain JE, Tuuli MG, Macones GA, Roehl KA, Odibo AO, Cahill AG. Risk factors for serious morbidity in term nonanomalous neonates. Am J Obstet Gynecol. 2015;212(6):799 e1–7.
Martinez-Biarge M, Cheong JL, Diez-Sebastian J, Mercuri E, Dubowitz LM, Cowan FM. Risk factors for neonatal arterial ischemic stroke: the importance of the intrapartum period. J Pediatr. 2016;173:62–8 e1.
Greenwell EA, Wyshak G, Ringer SA, Johnson LC, Rivkin MJ, Lieberman E. Intrapartum temperature elevation, epidural use, and adverse outcome in term infants. Pediatrics. 2012;129(2):e447–54.
Impey LW, Greenwood CE, Black RS, Yeh PS, Sheil O, Doyle P. The relationship between intrapartum maternal fever and neonatal acidosis as risk factors for neonatal encephalopathy. Am J Obstet Gynecol. 2008;198(1):49 e1–6.
O’Reilly D, Labrecque M, O’Melia M, Bacic J, Hansen A, Soul JS. Passive cooling during transport of asphyxiated term newborns. J Perinatol. 2013;33(6):435–40.
Fairchild K, Sokora D, Scott J, Zanelli S. Therapeutic hypothermia on neonatal transport: 4-year experience in a single NICU. J Perinatol. 2010;30(5):324–9.
Lodygensky GA, Battin MR, Gunn AJ. Mild neonatal encephalopathy—how, when, and how much to treat? JAMA Pediatr. 2018;172(1):3–4.
Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976;33(10):696–705.
Conway JM, Walsh BH, Boylan GB, Murray DM. Mild hypoxic ischaemic encephalopathy and long term neurodevelopmental outcome - a systematic review. Early Hum Dev. 2018;120:80–7.
•• Chalak LF, Nguyen KA, Prempunpong C, Heyne R, Thayyil S, Shankaran S et al. Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18–22 months. Pediatr Res. 2018 https://doi.org/10.1038/s41390-018-0174-x/. Accessed 13 Sep 2018.. Prospective cohort study quantifying the risk of disability and neurodevelopmental impairment after mild neonatal encephalopathy.
•• Murray DM, O’Connor CM, Ryan CA, Korotchikova I, Boylan GB. Early EEG grade and outcome at 5 years after mild neonatal hypoxic ischemic encephalopathy. Pediatrics. 2016;138(4) Cohort study showing similar risk of long term disabilty in infants with formally characterized mild and moderate encephalopathy.
Davidson JO, Battin M, Gunn AJ. Evidence that therapeutic hypothermia should be continued for 72 hours. Arch Dis Child Fetal Neonatal Ed. 2018:fetalneonatal-2018-315844.
• Lally PJ, Montaldo P, Oliveira V, Swamy RS, Soe A, Shankaran S, et al. Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2018;103(4):F383–F7 Small cohort study highlighting high rate of brain injury on magnetic resonance imaging in infants with mild encephalopathy who were rewarmed prematurely.
Davidson JO, Dean JM, Fraser M, Wassink G, Andelius TC, Dhillon SK, et al. Perinatal brain injury: mechanisms and therapeutic approaches. Front Biosci (Landmark Ed). 2018;23:2204–26.
Filippi L, Fiorini P, Catarzi S, Berti E, Padrini L, Landucci E, et al. Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI): a feasibility study. J Matern Fetal Neonatal Med. 2018;31(8):973–80.
Faulkner S, Bainbridge A, Kato T, Chandrasekaran M, Kapetanakis AB, Hristova M, et al. Xenon augmented hypothermia reduces early lactate/N-acetylaspartate and cell death in perinatal asphyxia. Ann Neurol. 2011;70(1):133–50.
• Azzopardi D, Robertson NJ, Bainbridge A, Cady E, Charles-Edwards G, Deierl A, et al. Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial. Lancet Neurol. 2016;15(2):145–53 Innovative randomized controlled trial showing no benefit from the combination of xenon plus hypothermia on magnetic resonance measured outcomes.
Aly H, Elmahdy H, El-Dib M, Rowisha M, Awny M, El-Gohary T, et al. Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J Perinatol. 2015;35(3):186–91.
Malla RR, Asimi R, Teli MA, Shaheen F, Bhat MA. Erythropoietin monotherapy in perinatal asphyxia with moderate to severe encephalopathy: a randomized placebo-controlled trial. J Perinatol. 2017;37(5):596–601.
Elmahdy H, El-Mashad AR, El-Bahrawy H, El-Gohary T, El-Barbary A, Aly H. Human recombinant erythropoietin in asphyxia neonatorum: pilot trial. Pediatrics. 2010;125(5):e1135–42.
Zhu C, Kang W, Xu F, Cheng X, Zhang Z, Jia L, et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. 2009;124(2):e218–26.
• Wu YW, Mathur AM, Chang T, McKinstry RC, Mulkey SB, Mayock DE, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: A phase II trial. Pediatrics. 2016;137(6):e20160191 A well conducted phase II trial showing benefit from combined treatement with erythropoeitin and hypothermia for neonatal encephalopathy.
Bennet L, Booth L, Gunn AJ. Potential biomarkers for hypoxic-ischemic encephalopathy. Semin Fetal Neonatal Med. 2010;15(5):253–60.
Funding
The authors’ work reported in this review has been supported by grants from the Health Research Council of New Zealand, New Zealand Lottery Grants Board, the Auckland Medical Research Foundation, the Neurological Foundation of New Zealand, the Norwegian Research Council, and the Moulton Foundation UK.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Laura Bennet, Joanne Davidson, Simerdeep Dhillon, Marianne Thoresen, Guido Wassink and Kelly Zhou each declare no potential conflicts of interest. Alistair J. Gunn reports a US patent 6,986,783 issued. Patent held by the University of Auckland.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Pediatric Neurology
Rights and permissions
About this article
Cite this article
Wassink, G., Davidson, J.O., Dhillon, S.K. et al. Therapeutic Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy. Curr Neurol Neurosci Rep 19, 2 (2019). https://doi.org/10.1007/s11910-019-0916-0
Published:
DOI: https://doi.org/10.1007/s11910-019-0916-0