Time to Adopt Cooling for Neonatal Hypoxic-Ischemic Encephalopathy: Response to a Previous Commentary

Time to Adopt Cooling for Neonatal Hypoxic-Ischemic Encephalopathy: Response to a Previous Commentary Max Perlman and Prakesh Shah Pediatrics 2008;121;616-618 DOI: 10.1542/peds.2007-3497

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/121/3/616

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2008 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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COMMENTARY

Time to Adopt Cooling for Neonatal HypoxicIschemic Encephalopathy: Response to a Previous Commentary Max Perlman, MB, BS, FRCPC, FRCPa,b, Prakesh Shah, MD, FRCPC, MRCPCHa,c a

Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; bDivision of Neonatology, Hospital for Sick Children, Toronto, Ontario, Canada; cDepartment of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada The authors have indicated they have no financial relationships relevant to this article to disclose.

O

N THE BASIS of opinions of problematic evidence,

Kirpalani et al stated that the “standard of care” criteria for adopting hypothermia for neonatal hypoxicischemic encephalopathy (HIE) had not been met. They argued for a “conservative approach.” Clinicians who are “impressed” by their evidence are not mandated to offer cooling and can ethically continue to randomly assign patients “into ongoing, or new trials.” Yet, the authors considered the evidence to be “certainly” sufficiently strong for cautious use of this treatment by clinicians who are “impressed with the results.” These apparently conflicting statements are reinforced by previous confusing statements by co-author Barks2: “Many of us, including this author and the lead author [Dr Shankaran] of the Network trial,[3] who caution against uncontrolled adoption of cooling, have lost equipoise, and we are now cooling babies who meet the eligibility criteria of our original trials,” and the semantically elusive, “In a small number of experienced centers, it is a novel therapy that has become ‘standard care’ (without randomization), but it is not yet the ‘standard of care’ (emphasis in the original). Evolution in this field has outdated this conservative approach. One cooling trial (Infant Cooling Evaluation [ICE])4 was stopped prematurely, the research protocol of another has been altered,5 a third trial (Trial of Whole Body Hypothermia for Perinatal Asphyxia [TOBY])6 was stopped at the end of the funding period before achieving its revised sample size, and 3 independent systematic reviews4,7,8 have confirmed the efficacy and safety of cooling. Today’s question is whether it is acceptable for individual hospitals or physicians to withhold from parents information about and access to cooling. We question the lingering concerns about the methodology of the trials raised by Kirpalani et al.1 The importance of the answer is illustrated by predictive calculations: Of the 15 to 18 infants born daily in the United States with moderate-to-severe asphyxia, 10 to 12 of them die or develop moderate-to-severe disability; providing hypothermia to all would likely prevent 3 infants from either death or moderate-to-severe disability without causing 616

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any clinically significant adverse effects.8 This is an enormous effect size. We address the issues raised by Kirpalani et al1 in the order in which they were presented originally. POTENTIAL FOR BIASES ARISING We agree that withdrawal of life support (or nonwithdrawal for patients with similar prognoses) is pivotal in determining the outcome of infants with HIE by tipping the balance between death and significant disability. In our experience, based on a well-defined, transparently documented process, the immediate cause of death was withdrawal of life support in 91% of infants with HIE who died after 8 hours of age.9 Kirpalani et al’s line of reasoning is that a reduced rate of withdrawal is expected to tip the balance, decreasing the death rate and increasing the severe disability rate among survivors. They acknowledged that the latter did not occur. Although withdrawal of intensive therapy occurred more frequently in the intervention group, there was no evidence that the cost of the reduced mortality rate was an increased disability rate; on the contrary, all outcomes improved.7,8,10 Thus, the “primum non nocere” principle was not violated. Kirpalani et al pointed out that the failure to demonstrate an increased morbidity rate does not exclude the possibility of underlying bias but made no mention of the potential for cooling to reduce the severity of the HIE, hence less reason for withdrawal of support. Kirpalani et al1 also mentioned the use of the comAbbreviation: HIE, hypoxic-ischemic encephalopathy Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees. Dr Perlman advised the principal investigators of the CoolCap trial but did not participate in the trial or recruit any patients.

www.pediatrics.org/cgi/doi/10.1542/peds.2007-3497 doi:10.1542/peds.2007-3497 Accepted for publication Nov 27, 2007 Address correspondence to Max Perlman, MB, BS, FRCPC, FRCP, 1711/175 Cumberland St, Toronto, Ontario, Canada M5R 3M9. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2008 by the American Academy of Pediatrics

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posite outcome end point as a source of potential bias but did not develop this point. In fact, the component outcomes of disability and death are different expressions of the same outcome, viz, severe brain injury (or a strong suspicion thereof). The terms “complementary outcomes” or “reciprocal outcomes” may be more appropriate than “composite outcome” in the HIE context. The components death and disability are both clinically important and carry similar weight (with the latter permitting withdrawal of support). Both are likely to be influenced by cooling, and together they characterize the net effect of the therapy. Reporting of the composite outcome in hypothermia trials conforms to the recommendations for the use and interpretation of composite outcomes.11 We agree with Kirpalani et al that criteria for withdrawal cannot be mandated in a clinical trial, but we disagree with the notion of blinded adjudication in a research context. It is unnecessary to audit the withdrawal process in this context; the great majority of physicians who are involved with the parents in decision-making are personally risk-aversive and do not participate in or implement withdrawal-of-support decisions unless the best interests of child and family are served. CONCERNS ABOUT THE MANAGEMENT OF CONTROL-GROUP PATIENTS Kirpalani et al indicated that a proportion of control patients had periods of hyperthermia and suggested that “some active cooling mechanism may be required to avoid excessive [body] temperatures.”1 In contrast, the control-group patients may have benefited from the Hawthorne effect. Kirpalani et al suggested avoiding hyperthermia but did not suggest how to do it. Some patients develop hyperthermia in response to brain injury,12 and the only way to control it would be to cool patients actively. Unless the results of ongoing trials change the results of additional meta-analyses,8 the new research advocated by Kirpalani et al will long delay decisions about care. INTERPRETATION OF SUBGROUP ANALYSIS We agree with the methodologic concerns of Kirpalani et al1 regarding the different subgroup criteria and the inadequate sample sizes. However, their critique of subgroup analyses has no bearing on the results of the primary outcome of the studies. OPTIMAL INFORMATION SIZE We challenge the calculated sample size of Kirpalani et al1 on 3 grounds: First, a choice of 80% rather than 90% power would have sufficed for a therapy not shown to have any clinically significant adverse effects.8 Second, the control event rate was 64%, not 61.3%.4,8 Third, the authors did no justify an arbitrary 50% primary outcome rate in controls, a rate that requires inclusion of patients with mild HIE. Recalculation of the required sample size on the basis of the above grounds is 482, and with more than the expected effect size (actual relative risk: 0.76 [ie, 24% effect size]), the sample size would be even

lower.8 Thus, the published trials certainly meet the suggested “optimal information size.” The authors reported historical instances of harmful interventions adopted prematurely but failed to mention the other side of the story. Failure to conduct metaanalyses and adopt new standards in an appropriate and timely fashion was described by Chalmers as a “scandalous failure of science to cumulate evidence scientifically.”13 Examples include the recommendation to adopt the supine sleeping position in 1970, which could have averted 50 000 cases of sudden infant death syndrome in Europe alone,14 and the use of streptokinase for myocardial infarction in 1973 (P ⬍ .01), which could have averted random assignment of the next 17 500 patients (in 25 trials) to control groups.15 We are obliged to navigate our patients between the extreme positions of precocious recognition of novel therapies and unjustifiable delay in instituting beneficial therapies. Clinicians and health care providers who make patient-care decisions and ethics and safety committees that make human-experimentation decisions may have difficulty explaining their disregard of the evidence (the significant results of trials and meta-analyses4,7,8) on the basis of the problems perceived by Kirpalani et al.1 Individual clinicians and institutions are obliged to review the evidence and make their own decisions, as did members of the network trial.2 It is time to stop postponing the decision to accept hypothermia (at experienced centers that use established protocols) as an effective treatment. It is our duty to explain the benefits and unknowns of cooling and to offer this treatment to every eligible patient with moderate or severe neonatal HIE. 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. Barks J. Neonatal hypothermia: what are we waiting for? Available at: www.nicuniversity.org/downloads/Neonatal㛭 Hypothermia.pdf. Accessed November 17, 2007 3. Shankaran S, Laptook A, Wright LL, et al. Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants. Pediatrics. 2002;110(2 pt 1):377–385 4. Jacobs SE. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. J Pediatr. 2005;147(1):122–123 5. Simbruner G. Induced systemic hypothermia in asphyxiated new-born infants: a randomized, controlled, multicenter study. Available at: www.neonatal-research.at/php/detail.php? artnr⫽4367&ukatnr⫽11410&ukatname⫽Current%20research. Accessed November 24, 2007 6. Imperial College London, Clinical Co-ordinating Centre. TOBY Study protocol: whole body hypothermia for the treatment of perinatal asphyxial encephalopathy. Available at: www. npeu.ox.ac.uk/toby/toby㛭downloads/toby㛭fullprotocol.pdf. Accessed October 13, 2007 7. Schulzke SM, Rao S, Patole SK. A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy: are we there yet? BMC Pediatr. 2007;7:30 8. Shah PS, Ohlsson A, Perlman M. Hypothermia to treat neonatal hypoxic ischemic encephalopathy: systematic review. Arch Pediatr Adolesc Med. 2007;161(10):951–958

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9. Shah PS, Beyene J, To T, Ohlsson A, Perlman M. Postasphyxial hypoxic-ischemic encephalopathy in neonates: outcome prediction rule within 4 hours of birth. Arch Pediatr Adolesc Med. 2006;160(7):729 –736 10. Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2007;(4):CD003311 11. Ferreira-Gonza´lez I, Permanyer-Miralda G, Busse JW, et al. Methodologic discussions for using and interpreting composite endpoints are limited, but still identify major concerns. J Clin Epidemiol. 2007;60(7):651– 657; discussion 658 – 662

12. Dietrich WD, Bramlett HM. Hyperthermia and central nervous system injury. Prog Brain Res. 2007;162:201–217 13. Chalmers I. The scandalous failure of science to cumulate evidence scientifically. Clin Trials. 2005;2(3):229 –231 14. Gilbert R, Salanti G, Harden M, See S. Infant sleeping position and the sudden infant death syndrome: systematic review of observational studies and historical review of recommendations from 1940 to 2002. Int J Epidemiol. 2005;34(4):874 – 887 15. Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mosteller F, Chalmers TC. Cumulative meta-analysis of therapeutic trials for myocardial infarction. N Engl J Med. 1992;327(4):248 –254

ANTIDEPRESSANTS UNDER SCRUTINY OVER EFFICACY: SWEEPING OVERVIEW SUGGESTS SUPPRESSION OF NEGATIVE DATA HAS DISTORTED VIEW OF DRUGS “The effectiveness of a dozen popular antidepressants has been exaggerated by selective publication of favorable results, according to a review of unpublished data submitted to the Food and Drug Administration. As a result, doctors and patients are getting a distorted view of how well blockbuster antidepressants like Wyeth’s Effexor and Pfizer Inc.’s Zoloft really work, researchers asserted in this week’s New England Journal of Medicine. Since the overwhelming amount of published data on the drugs show they are effective, doctors unaware of the unpublished data are making inappropriate prescribing decisions that aren’t in the best interest of their patients, according to researchers led by Erick Turner, a psychiatrist at Oregon Health & Science University. Sales of antidepressants total about $21 billion a year, according to IMS Health. Wyeth and Pfizer declined to comment on the study results. Both companies said they had committed to disclose all study results, although not necessarily in medical journals. GlaxoSmithKline PLC, maker of Wellbutrin and Paxil, said it has posted the results of more than 3,000 trials involving 82 medications on its Web site, and also has filed information on 1,060 continuing trials at a federal government Web site. Schering-Plough Corp., whose Organon Corp. unit markets Remeron, and Eli Lilly & Co., which makes Prozac, said their study results were indeed published—not individually, but as part of larger medical articles that combined data from more than one study at a time. The New England Journal study counted a clinical trial as published only if it was the sole subject of an article. ‘Lilly has a policy that we disclose and publish all the results from our clinical trials, regardless of the outcomes from them,’ a Lilly spokeswoman said. Pharmaceutical companies are under no obligation to publish the studies they sponsor and submit to the FDA, nor are the researchers they hire to do the work. The researchers publishing in the New England Journal were able to identify unpublished studies by obtaining and comparing documents filed by the companies with the FDA against databases of medical publications.” Armstrong D and Winstein KJ. Wall Street Journal. January 17, 2008 Editor’s Note: Sir Ian Chalmers and others have been calling attention to this important problem for years. It should be stopped. Noted by JFL, MD

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Time to Adopt Cooling for Neonatal Hypoxic-Ischemic Encephalopathy: Response to a Previous Commentary Max Perlman and Prakesh Shah Pediatrics 2008;121;616-618 DOI: 10.1542/peds.2007-3497 Updated Information & Services

including high-resolution figures, can be found at: http://www.pediatrics.org/cgi/content/full/121/3/616

References

This article cites 11 articles, 6 of which you can access for free at: http://www.pediatrics.org/cgi/content/full/121/3/616#BIBL

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