Cooling for Neonatal Hypoxic Ischemic Encephalopathy: Do We Have the Answer?

The neonatal community deserves congratulations for responding vigorously to Silverman's1 call for randomized controlled trials (RCTs) to evaluate neonatal therapies. Although more trials are still needed,2 existing RCTs present new challenges in interpretation. One of the most vexing is when to proclaim innovative therapies as “standard of care.”The neonatal critical care community faces this challenge in evaluation of hypothermia as treatment for hypoxemic-ischemic encephalopathy (HIE).3–5 National bodies have made declarations that the neonatal community should consider hypothermia experimental pending completion of current ongoing trials.6–9 Although the influence of these bodies is considerable, individual physicians and sites apparently feel pressure to “do something” in the very dire circumstances of HIE in the newborn. In an informal sample of convenience, we have found that some centers are performing cooling, either with or without informed consent. Although many clinicians concur with the leading bodies that state there is a need for additional trials, it is confusing for practicing neonatologists when some members of these bodies also publicly state that they are actively providing cooling therapy.If leading centers are promoting active cooling, they have, in effect, adopted cooling as a standard of care. This may not only have legal implications but also raises ethical issues for those who believe the right thing to do currently is to continue performing RCTs. The countervailing argument is that to not offer cooling as standard therapy for such a devastating disease as HIE is itself, unethical. These opposing viewpoints are not easily resolvable except by considering what the overall benefit of eliminating residual doubt, one way or the other, would be. Our concern is that advocacy of hypothermia as a standard of care represents an excessively low threshold for accepting promising therapies and will ultimately lead to resources devoted to useless interventions that should be devoted to developing and implementing useful ones.We argue for a conservative approach to declaring a therapy to be standard of care. Although individual clinicians may choose to implement a therapy for which the magnitude of benefit remains uncertain, designating a therapy as a standard for quality care mandates the presence of very strong evidence. In this commentary, we explain the reasoning behind our approach and propose guidelines for considering when a body of meta-analytical data is strong enough to argue that it is unethical to further randomize into ongoing, or new trials.Why do we advocate a conservative stance? The history of physicians’ repeated endorsement of therapies that later proved useless or harmful,10 including therapies that seemed promising in RCTs,11 provides one compelling rationale. Ioannidis11 reported, after reviewing highly cited publications of efficacious studies, that 32% were later found to have been contradicted or to have had initially stronger effects. The studies that were highly cited and not refuted had a median sample size of 1542, as opposed to those that were either contradicted or claimed initially stronger effects, which had a median sample size of 624.In addition to the sobering lessons of subsequent reversal of initially promising results, our arguments for caution regarding hypothermia rest on limitations in the internal validity of the 2 pivotal trials, the Gluckman et al Cool Cap study,3 and the Shankaran et al National Institute of Child Health and Human Development (NICHD) whole-body–cooling study,4 and 1 smaller pilot study of 65 infants by Eicher et al.5 We are aware of 1 other pilot study12 and 1 completed but unpublished study.13 A final study, the Trial of Whole Body Hypothermia for Perinatal Asphyxia (TOBY),14 has completed recruitment but still has to achieve target end points of 18 months’ outcome. We consider the implications of results of these smaller and unpublished studies in “Have the Pooled Studies Achieved an Optimal Information Size?” below.Researchers in the Cool Cap study found, with a subgroup analysis, a reduction in 18 months’ adverse outcome. Using whole-body cooling, Shankaran et al found an overall reduction in adverse outcomes at 18 months (relative risk [RR]: 0.72 [95% confidence interval (CI): 0.54–0.95]; P = .01). Although similar in basic goals, the 2 studies had important differences6,7 in how they achieved cooling (whether head3 or whole-body4,5 cooling) and in the entry criteria. The Cool Cap trial used amplitude-integrated electroencephalography (aEEG) to discern whether infants were affected enough to randomly assign them.3 These differences do not necessarily preclude a pooled analysis of all enrolled infants irrespective of subgroup, making a total of 478 infants; infants cooled had a 0.76 RR (as compared with control infants) for the outcome of death or disability at 12 to 18 months.15Although these results seem compelling on the surface, 4 key concerns remain: (1) the potential for biases that arises within an unblinded study; (2) concern about the management of control-group patients; (3) how to interpret subgroup analysis; and (4) the relatively small number of patients studied to date. In summary, exciting potential exists in hypothermia for cooling. Is the evidence sufficiently strong that clinicians impressed with the results may cautiously use this treatment for neonatal encephalopathy while they wait for the many questions around its optimal use to be answered? Certainly. On the other hand, the neonatal community continuing with a conservative approach to declaring a new standard of care will avoid unfortunate mistakes of premature dissemination of experimental management strategies. In both adults and children with traumatic brain injury, cooling has not fulfilled its earlier promise. We should demand strong evidence of robust, consistent effects in highly valid studies that have enrolled adequate numbers of patients before mandating a new therapy for management of all relevant patients. The evidence for cooling fails to meet this standard.Dr Barks, as a site investigator for Mott Hospital, recruited infants for the Cool Cap study; Dr Kirpalani was a site investigator for McMaster University Hospital and recruited infants for the ICE study.We acknowledge valuable methodologic advice from Dr Barbara Schmidt and Dr Edmund Hey.