The Journal of Pediatrics
Volume 157, Issue 3 , Pages 351-352, September 2010

Hypothermic Neural Rescue: Work Continues

  • A. David Edwards, FMedSci

      Affiliations

    • Corresponding Author InformationReprint requests: A. David Edwards, FMedSci, Department of Pediatrics, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
    • ,
  • Denis V. Azzopardi, MD

Institute of Clinical Sciences, Imperial College London, Medical Research Council Clinical Sciences Centre, Hammermmith Hospital, London, UK

published online 26 July 2010.

Article Outline

aEEG, Amplitude-integrated electroencephalopathy, ECMO, Extracorporeal membrane oxygenation

 

See related articles, p 361, p 367, and p 499

The publication of several major randomized controlled trials and a meta-analysis of all available data have at last shown that reducing body temperature in infants with perinatal asphyxia reduces death and disability and increases the chance of normal survival, at least to 2 years of age.1, 2, 3, 4, 5 Although we are awaiting publication of 6-year follow-up data from the major trials, there is every reason to believe that these beneficial effects of treatment will persist, not in the least because large magnetic resonance imaging datasets have shown significantly less structural brain damage in cooled infants.6 The treatment is cost- effective in developed health economies,7 and many countries either have, or are in the process of developing, implementation packages for this new treatment.

This issue of The Journal presents 3 articles that add to our understanding of hypothermic therapy in different ways. Zhou et al8 report a phase III trial of selective head cooling after asphyxia in China. Filipi et al9 provide data on the use of topiramate in the context of postasphyxial hypothermia. A case series from Massaro et al10 records their observations of infants requiring extracorporeal membrane oxygenation (ECMO) therapy during hypothermic neural rescue.

At first glance, the trial reported by Zhou et al8 appears to be a confirmation of the CoolCap study published in 20054 which used a head cooling device to achieve moderate body hypothermia, starting within 6 hours of delivery and continuing for 72 hours afterward. Consistent with the current meta-analysis, the primary outcome of death or disability at 18 months was significantly reduced in the treatment group. However, some differences between the two studies make direct comparison difficult. The entry criteria were different, and Zhou et al8 point out that their groups were less severely affected compared with those in other major trials. The structure of the cohort is also unusual; along with a low death rate related to moderate insult severity, infants were excluded for evidence of infection (very loosely defined), and an excess of male infants was recruited to the trial (85%). The trial had a high rate of noncompletion, with follow-up data available for only 194 of 256 enrolled infants (75%). Twenty-one infants were excluded because of protocol violations, casting doubt on the authors' assertions that analysis was by intention to treat.

These issues argue for caution in interpretation. However, it is interesting to note that both major trials that used amplitude-integrated electroencephalography (aEEG) to confirm the severity of encephalopathy (CoolCap and TOBY) were underpowered with respect to the primary outcome. In contrast, the smaller National Institute of Child Health and Human Development trial and the trial of Zhou et al8 used only clinical criteria for patient enrollment and found a positive effect on birth asphyxia. This finding may support those who have argued that aEEG selects out a severely affected group that is less susceptible to benefits of treatment. It also can be speculated that by reducing the interactive effects of infection and hypoxia-ischemia, the trial of Zhou et al8 includes patients for whom treatment is effective.11 However, what that trial does not do is add weight to either selective head or total body cooling as a mode of therapy, both methods of cooling appear to work effectively, and the decision to choose one or the other should be made on grounds other than efficacy.1

The trials of Zhou et al8 also reminds us that decisions about medical interventions are made in widely diverse social contexts, and neither physicians nor their patients are immune to social pressure. Therapeutic research must be considered in context; a recent pilot study of cooling in Uganda suggested a less significant effect than reported previously.12 Further investigations are urgently needed if hypothermic neural rescue is to be brought safely to infants worldwide.

The importance of hypothermia is not just that it offers a treatment where previously there was none. Indeed, a considerable proportion of treated infants still die or develop neurologic problems. The real success of hypothermia is to give proof of concept that neural rescue is possible, and many researchers are now evaluating additional therapies that will improve outcomes. Fortunately, 3 decades of bench research has created a list of potential neuroprotective drugs, some of which (eg, xenon) are currently in early-phase trials.13 Topiramate, an oral anticonvulsant with marked neuroprotective properties, would be a good choice for a clinical trial. Thus, it is helpful to have pharmacokinetic data in infants with hypothermia, as is provided by Filipi et al9 in this issue of The Journal. The authors provide detailed information on the plasma levels of two different drug doses at two levels of hypothermia. Because this is a nonrandomized observational study with nonstandard cooling methods and the coadministration of other drugs, it would be wrong to overinterpret the differences between groups; nevertheless, the pharmacokinetic profiles will be valuable to researchers considering neuroprotective trials of topiramate.

The authors, rather hopefully, describe their work as a “safety study,” but even large randomized trials often are too small to detect adverse reactions. These are found in later meta-analysis or postmarketing surveillance. Certainly the registries run by the Vermont-Oxford Network in the United States and the TOBY group in the United Kingdom provide valuable resources for detecting the adverse effects of both hypothermia and additional therapies. It is important that all clinicians who use hypothermic therapy submit their data to these registries to facilitate the accumulation of information and knowledge.

A well-known example of the value of registries in evaluating new therapies is the ECMO registry. We anticipate that the third report on hypothermia in this issue of The Journal will be reporting their cases to that registry. Massaro et al10 offer a small case series of their use of ECMO in 5 infants whose respiratory function deteriorated during hypothermic neural rescue. This is a separate indication from the use of hypothermia to improve neurodevelopmental outcomes in infants requiring ECMO, which is being investigated by the NEST trial. The results of major hypothermia trials suggest that the need for ECMO during hypothermia is rare; however, so the evidence might be limited to observational data for a considerable time.

There is a sense that a page is turning for hypothermic neural rescue. All of the major trials of which we are aware have reported, at least in abstract form. The emphasis is now moving to new experimental studies of adjuvant therapies and health service research of the applicability of cooling in different environments. Now that we have convincing evidence that neural rescue therapy is possible, we should see more groups from around the world adding to the evidence base with a wide variety of studies. We can anticipate continued progress in reducing the incidence of death and disability in infants experiencing perinatal asphyxia.

Back to Article Outline

References 

  1. 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
  2. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009;361:1349–1358
  3. Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA, et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2005;32:11–17
  4. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005;365:663–670
  5. 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;353:1574–1584
  6. Rutherford M, Ramenghi LA, Edwards AD, Brocklehurst P, Halliday H, Levene M, et al. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol. 2010;9:39–45
  7. Regier D, Petrou S, Henderson J, Edamma O, Patel N, Strohm B, et al. Cost-effectiveness of therapeutic hypothermia to treat neonatal encephalopathy: results from the TOBY trial. Value Health 2010, in press.
  8. Zhou W-h, Chen G-q, Shao X-m, Liu X-z, Shan R-b, Zhuang D-y, et al. Selective head cooling with mild systemic hypothermia after neonatal hypoxic-ischemic encephalopathy: a multicenter randomized controlled trial in China. J Pediatr. 2010;157:367–372
  9. Filippi L, Poggi C, la Marca G, Furlanetto S, Fiorini P, Cavallaro G, et al. Oral topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia: a safety study. J Pediatr. 2010;157:361–366
  10. Massaro A, Rais-Bahrami K, Chang T, Glass P, Short BL, Baumgart S, et al. Therapeutic hypothermia for neonatal encephalopathy and extracorporeal membrane oxygenation. J Pediatr. 2010;157:499–501
  11. Eklind S, Mallard C, Leverin AL, Gilland E, Blomgren K, Mattsby-Baltzer I, et al. Bacterial endotoxin sensitizes the immature brain to hypoxic-ischaemic injury. Eur J Neurosci. 2001;13:1101–1106
  12. Robertson NJ, Nakakeeto M, Hagmann C, Cowan FM, Acolet D, Iwata O, et al. Therapeutic hypothermia for birth asphyxia in low-resource settings: a pilot randomised controlled trial. Lancet. 2008;372:801–803
  13. Cilio MR, Ferriero DM. Synergistic neuroprotective therapies with hypothermia. Semin Fetal Neonatal Med. 2010;[Epub ahead of print]

PII: S0022-3476(10)00520-2

doi:10.1016/j.jpeds.2010.06.029

Refers to article:

  • Outcomes and Causes of Death in Children on Home Mechanical Ventilation via Tracheostomy: An Institutional and Literature Review , 16 August 2010

    Jeffrey D. Edwards, Sheila S. Kun, Thomas G. Keens
    The Journal of Pediatrics December 2010 (Vol. 157, Issue 6, Pages 955-959.e2)

  • Oral Topiramate in Neonates with Hypoxic Ischemic Encephalopathy Treated with Hypothermia: A Safety Study , 31 May 2010

    Luca Filippi, Chiara Poggi, Giancarlo la Marca, Sandra Furlanetto, Patrizio Fiorini, Giacomo Cavallaro, Angela Plantulli, Gianpaolo Donzelli, Renzo Guerrini
    The Journal of Pediatrics September 2010 (Vol. 157, Issue 3, Pages 361-366)

  • Selective Head Cooling with Mild Systemic Hypothermia after Neonatal Hypoxic-Ischemic Encephalopathy: A Multicenter Randomized Controlled Trial in China , 20 May 2010

    Wen-hao Zhou, Guo-qiang Cheng, Xiao-mei Shao, Xian-zhi Liu, Ruo-bing Shan, De-yi Zhuang, Cong-le Zhou, Li-zhong Du, Yun Cao, Qun Yang, Lai-shuan Wang, China Study Group
    The Journal of Pediatrics September 2010 (Vol. 157, Issue 3, Pages 367-372.e3)

The Journal of Pediatrics
Volume 157, Issue 3 , Pages 351-352, September 2010

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