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LETTER TO THE EDITOR |
Trevor Duke, MBBS, MD, FRACP
Centre for International Child Health
Department of Paediatrics
University of Melbourne
Parkville, Victoria 3052, Australia
To the Editor.—
Recently, Blackmon et al1 reviewed the current evidence for the effectiveness and safety of hypothermia in newborns with hypoxic-ischemic encephalopathy (HIE). They urged caution in the interpretation of recently published randomized, controlled trials and argued that ongoing controlled trials of hypothermia should be completed. However, is it ethical for these trials to continue?
All 3 trials of mild systemic hypothermia for infants with HIE showed a substantial reduction in the combined outcome of death or disability in neonates managed with hypothermia.2–4 In the published trials there were differences in methods for inducing hypothermia, inclusion criteria, and follow-up, but they have shown consistent benefit. These studies have been described as imperfect but also as well constructed and well analyzed.5 Furthermore, as highlighted in the Blackmon et al review, there is substantial evidence from animal models and adult humans that hypothermia attenuates neurologic injury after hypoxia.1
Several recently published editorials have argued along with Blackmon et al that enrollment in controlled trials of hypothermia should continue.5–7 They have pointed to heterogeneity in the published trials, the borderline statistical significance of the results, the relatively short-term outcome measures, and ongoing uncertainties about which type of cooling should be used and in which infants.
However, 2 fundamental issues have been neglected by the authors of these editorials: the risk to infants who are involved in ongoing trials of hypothermia and whether parents are giving truly informed consent.
If trial results are combined, the relative risk of death or disability for hypothermia is 0.76 (confidence interval: 0.65–0.89),5 which corresponds to a number needed to treat of 6.7 infants. On the basis of existing data, for every 100 infants with moderate or severe HIE randomly assigned to a normothermia group, 15 additional infants (confidence interval: 7–23) will die or have significant disability at 18 months.
For ongoing trials to be ethical they must ensure informed consent by parents. Parents need to be aware of the apparent increased risk of death or disability associated with being randomly assigned to normothermia. For at least 2 of the 3 ongoing trials there has been little or no modification to the information statement given to parents in light of the newly published trials.
We believe that the strength of the existing evidence warrants careful consideration of whether the risks to participants involved in continuing trials are justified. The inherent conflict between the need to generate the best scientific evidence to guide therapy and the need to protect the well-being of research participants sometimes means that it is not possible to reach as high a level of statistical certainty as would be desirable.
Blackmon et al highlighted 8 unanswered questions about hypothermia; however, only the last of these questions (concerning the long-term follow-up of cooled infants) might be answered by completing studies that are currently underway. Future trials comparing methods and levels of cooling and duration of hypothermia will be necessary, but these will not require a normothermic control group. The current controlled trials should cease, and the interim results should be pooled into a meta-analysis with the published trials. Such worldwide cooperation in science would provide an opportunity to balance the interests of newborn infants and their families with the interests of institutions and investigators.
FOOTNOTES
Conflict of interest: The authors declare that they have no financial interests relevant to the topics in this manuscript. Several of the authors (Drs Wilkinson, Casalaz, Watkins, and Andersen) have been involved in a randomized, controlled trial of hypothermia for hypoxic-ischemic encephalopathy.
REFERENCES
This article has been cited by other articles:
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  P. S. Shah, A. Ohlsson, and M. Perlman Hypothermia to Treat Neonatal Hypoxic Ischemic Encephalopathy: Systematic Review Arch Pediatr Adolesc Med, October 1, 2007; 161(10): 951 - 958. [Abstract] [Full Text] [PDF]
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