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Post-publication Peer Reviews to:
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![[Read P3R]](/icons/misc/sectionDOWN.gif){kind=icon}
Cooling for neonatal encephalopathy
How certain do the parents want us to be?
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Denis Azzopardi, Senior Lecturer in Paediatrics Imperial College London, UK, A David Edwards
Send letter to journal:
d.azzopardi{at}imperial.ac.uk Denis Azzopardi, et al.
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Kirpalani et al (1) offer a detailed but guarded interpretation of the evidence that hypothermia is beneficial for infants with neonatal encephalopathy. We agree with most of these cautions and have long highlighted them at Conferences and in print (2). However, other analysts of the same datasets have reached quite different conclusions. Shah et al (3) believe the supporting evidence is now conclusive and strongly support hypothermic treatment; although Jacobs et al (4), while finding the data broadly positive emphasise that further data are needed. While we prefer meta-analyses which apply using the ‘intention to treat’ principle, we understand that there are differences in interpretation and potential for confusion. In the face of our happy agreement with Kirpilani et al, it seems surprising that they should the charge us and the other researchers who developed hypothermic neuroprotection from animal experiments to the proof of concept trials they now review with being disingenuous by recommending to national bodies that cooling should not presently be the standard of care and while providing this treatment to our patients. We can reassure them that we are fully aware of the uncertainties involved in moving from experiment to clinical practice. After the CoolCap and NICHD studies (5,6) became public there was a concerted effort to engage with colleagues, much aided by staff of the NICHD and other major bodies, and a widely published consensus of all the major groups which defined cooling as an evolving therapy in need of further investigation (7,8). Nevertheless, pediatricians will recognise that practical medicine is a series of decisions based on evolving evidence. In the face of current uncertainty, while waiting for more data the community has established a mechanism to underpin rational practice. In the USA the Vermont-Oxford Network, and in the UK the TOBY study (9) Investigators, have set up formal registries, and produced data collection forms and guidance on the management of cooled infants (10). These provide support to clinicians without influencing the decision on whether to provide hypothermic treatment. This is a rational and ethical approach for dealing with evidence that is, as Kirpalani et al acknowledge, suggestive while not conclusive. While we do not disagree with the conventional call that all treated infants should be included in properly established trials, Kirpalani et al should be aware of the significant financial implications of this statement, and that no funding body has yet agreed to resource further trials. References (1) Kirpalani H, Barks J, Thorlund K, Guyatt G. Cooling for Neonatal Hypoxic ischemic encephalopathy: Do We Have the Answer? Pediatrics 2007;120(5):1126-1130. (2) Azzopardi D, Edwards AD. Hypothermia. Seminars in Fetal and Neonatal Medicine 2007; 12(4):303-310. (3) Shah PS, Ohlsson A, Perlman M. Hypothermia to treat neonatal hypoxic ischemic encephalopathy: systematic review. Arch Pediatr Adolesc Med. 2007 Oct; 161(10):951-8. (4) Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews 2007, Issue 4. (5) 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(9460):663-70. (6) 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. (7) Higgins R, Raju TN, Perlman J et al. Hypothermia and perinatal asphyxia: executive summary of the National Institute of Child Health and Human Development workshop. J Pediatr 2006; 148(2):170-175. (8) Blackmon LR, Stark AR, and the Committee on Fetus and Newborn, American Academy of Pediatrics. Hypothermia: A Neuroprotective Therapy for Neonatal Hypoxic-Ischemic Encephalopathy. Pediatrics 2006; 117(3): 942- 948. (9) http://clinicaltrials.gov/ct/show/NCT00147030 (10) www.npeu.ox.ac.uk/tobyregister Conflict of Interest:Prof Edwards and Dr Azzopardi are investigators in the CoolCap and TOBY trials and Dr Azzopardi is a Prinicipal Investigator of the TOBY trial. |
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Nick Evans, Neonatologist Royal Prince Alfred Hospital and University of Sydney
Send letter to journal:
nevans{at}med.usyd.edu.au Nick Evans
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Dear Sir, Many of the same arguments now being put forward about hypothermia were used in some regions of the world against the use of antenatal steroids during the 1970’s and 80’s. That so many premature babies died or were maimed unnecessarily by the late adoption of this treatment is just as much a tragedy (and a disgrace) as the oft quoted examples of ineffective or harmful treatments that were adopted too early. The methodologies of clinical trials most often show that treatments have no effect. Under this prevailing weight of therapeutic nihilism, it can be hard to believe that something might actually work. While agreeing with the issues of uncertainty about the effects of hypothermia expressed by Kirpalani et al,[1] I am concerned that it is us the providers and the researchers that are setting the bar of certainty here. The missing step here would be to ask potential consumers of this therapy: How certain do you want us to be? In our own experience the answer to this question was pretty unequivocal. Our NICU was part of the now discontinued ICE trial. When the results of the NICHD and CoolCap study became available, we felt obliged to inform parents of these results during the consent process. The usual reaction was to query why we were still doing this trial. Our response was a lay version of the uncertainties as outlined by Kirpalani et al.[1] Most looked unconvinced and some became very upset when their baby drew the control arm and were told we were not offering this treatment outside a trial. We became increasingly uncomfortable with this and resolved to put the question back to our Hospital Research Ethics Committee, which has both scientific and consumer representation. We provided them with our own systematic review, which showed the same result as the recently published Cochrane update,[2] and we asked the question of the committee whether it was ethical to offer this treatment outside the trial. The answer was unequivocally that it was ethical. We continued to try to recruit to the ICE trial but found, once we had mentioned the trial results to date, no one wanted to consent even when we worked through the uncertainties. No- one is going to consent to participate in more trials. Most issues in healthcare are now rightly considered in a partnership between providers and consumers. It is our job as providers to advise consumers but it is also our responsibility to listen to them. The mechanisms for doing this in the context of applying evidence into practice are not there. Changing that will not be easy but maybe it’s something we should be working towards. Evidence based medicine is about applying the best available evidence into practice, this will change with time and the results from those babies recruited to the TOBY and ICE trials will be important additions to our knowledge. We need to acknowledge that these results may change the conclusion of the current Cochrane Review [2] that hypothermia appears to reduce death and disability after HIE. Until then our NICU, like many others, will feel obliged to offer this therapy to appropriate babies. Nick Evans References 1. Kirpalani H, Barks J, Thorlund K, Guyatt G. Cooling for Neonatal Hypoxic Ischemic Encephalopathy: Do We Have the Answer? Pediatrics 2007; 120: 1126-1130. 2. Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD003311. DOI: 10.1002/14651858.CD003311.pub2. Conflict of Interest:None declared |
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