PEDIATRICS Vol. 121 No. 3 March 2008, pp. 648-649 (doi:10.1542/10.1542/peds.2007-3310)
LETTER TO THE EDITOR |
Hypothermia: An Evolving Treatment for Neonatal Hypoxic Ischemic Encephalopathy
Alistair J. Gunn, MBChB, PhDDepartments of Physiology and Paediatrics
University of Auckland
Auckland 1023, New Zealand
Thomas Hoehn, MD, PhD
Neonatology and Pediatric Intensive Care Medicine
Department of General Pediatrics
Heinrich-Heine-University
D-40225 Duesseldorf, Germany
Georg Hansmann, MD, PhD
Department of Pediatrics
University of California
San Francisco, CA 94143
Christoph Bührer, MD, PhD
Universitäts-Kinderspital beider Basel
CH-4005 Basel, Switzerland
Georg Simbruner, MD
Department of Neonatology
University of Innsbruck
6020 Innsbruck, Austria
Jerome Yager, MD, FRCP(C)
Department of Pediatrics
Stollery Children's Hospital
University of Alberta
Edmonton, Alberta, Canada T6G 2J3
Malcolm Levene, MD
Academic Department of Paediatrics
University of Leeds
Leeds LS2 9NS, United Kingdom
Shannon E. G. Hamrick, MD
Department of Pediatrics
Emory University
Atlanta, GA 30322
Seetha Shankaran, MD
Wayne State University School of Medicine
Children's Hospital of Michigan and Hutzel Women's Hospital
Detroit, MI 48201
Marianne Thoresen, MD, PhD
Child Health at CSSB
University of Bristol
Bristol BS2 8EG, United Kingdom
To the Editor.—
It has always been challenging to know when new therapies should be considered ready for use in practice. History has provided many contrasting examples of simple and effective treatments (such as phototherapy and antenatal steroids) that languished for decades before being adopted and treatments that were and often continue to be used well after they proved to be either useless or less effective than simpler alternatives. However, it is extremely difficult to understand why Kirpalani and colleagues1 are so concerned that some neonatologists are now choosing to offer therapeutic hypothermia on a compassionate basis. Neither these practitioners nor any official body have, to our knowledge, declared that hypothermia should be the standard of care. They, and several of the undersigned, helped develop the consensus of the 2005 National Institute of Child Health and Human Development workshop that hypothermia is an evolving (not unproven or experimental) therapy, with many questions around its optimal use.2 Thus, the underlying premise of their commentary is shaky.
Three independent systematic reviews published this year have concluded that (1) therapeutic hypothermia can significantly reduce both death and medium-term disability after perinatal encephalopathy, (2) is safe, and (3) its outcomes are homogenous both within and between trials.3–5 Overall, although analysis strategies varied, reliable published information is available on 
638 randomly assigned infants for mortality and 506 for death or disability.5 Kirplani and colleagues seemed to suggest, somewhat arbitrarily, that perhaps 692 infants would be enough for reasonable certainty.1 If we may note the further outcome data from 157 randomly assigned infants that have been publically presented but not yet published (and are concordant with the current meta-analysis6) this target seems to have been broadly achieved.
Although new randomized trials are both highly unlikely and arguably inappropriate, we anticipate that information on nearly as many more infants again will become available over the next 3 years from existing completed trials.5 How likely is it that these trials will change the current consensus? If, at 1 extreme, there was no apparent effect in the next 600 children (bringing the total to a conservative 11061), with a 60% adverse control event rate, the relative risk (95% confidence interval) would go from 0.76 (0.65–0.89); P = .006)5 to 0.89 (0.8–0.98); P = .017). This estimate does not include unpublished data6; the estimates would be correspondingly more favorable if they were included. Thus, the current finding of benefit is already strikingly robust.3–5
The remaining issues raised by Kirpalani et al are of dubious relevance. The consistent a priori concern for these trials was that inappropriate prolongation of care in treated patients would lead to increased survival rates of disabled infants. Reassuringly, in the event, there was a reduction in disability rates in survivors.3 In addition, several of the authors can personally attest that all acute deaths in the CoolCap and National Institute of Child Health and Human Development trials were attributable to either overwhelming systemic complications or withdrawal of invasive care with compelling evidence of profound, unrecoverable neurologic injury. First, the few deaths in later infancy were related to complications of profound disability such as aspiration and tended to be fewer in treated infants.7,8 Next, the meta-analyses were based entirely on prospective, intention-to-treat recruitment of all patients without subgroup selection. Finally, all control infants in the major trials received the best available, optimal conventional care. Pyrexia occurs in a significant subset of control infants.9 Although the relationship of pyrexia with outcome may be partly noncausal, it is likely from experimental data that pyrexia is as deleterious as hypothermia is beneficial.10 However, there is no known strategy that is likely to successfully prevent all increases in infant temperature, although, speculatively, active cooling to the lower half of the reference range might achieve this. Realistically then, Kirpalani and colleagues1 are merely proposing that clinicians should cool, but to a lesser degree.
On this background is it now timely for practicing clinicians to ask whether they may, in consultation with and with consent from affected families, cautiously use this first treatment for neonatal encephalopathy while they wait for the many questions around its optimal use to be answered? It is our personal view that, given the robust evidence for benefit from current meta-analyses, the remarkable safety profile, the strong foundation in basic science,10 and supporting evidence from related disease states such as encephalopathy after cardiac arrest,11,12 the answer is now yes.
FOOTNOTES
Statements appearing here are those of the writers and do not represent the of.cial position of the American Academy of Pediatrics or its Committees. Comments on any topic, including the contents of PEDIATRICS, are invited from all members of the profession; those accepted for publication will not be subject to major editorial revision but generally must be no more than 400 words in length. The editors reserve the right to publish replies and may solicit responses from authors and others.
Please see www.pediatrics.org for instructions on submitting letters.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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