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Medicine at the limits of evidence: the fundamental limitation of the randomized clinical trial and the end of equipoise

Journal of Perinatology volume 34, pages 249–251 (2014)Cite this article

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Evidence-based medicine has inherent limits when applied to patient care. In this article we address one of those fundamental limitations as it relates to the newest evidence regarding oxygen-saturation targeting in the extremely low gestational age infant. The classic ‘strength of evidence’ pyramid relates to the evidence for treatment of a disease, but is limited to describing the typical response in a generalized patient. We propose a more complete model to rank the strength of evidence as it applies to direct care of the individual affected patient. Recently, neonatology seems to have painted itself into a corner. Attempts to finesse an answer to the decades-old question of the best supplemental oxygen targets for extremely low gestational age newborn (ELGANs) have yielded an unfortunate answer, at least for champions of lower saturation goals. Two of the three international randomized trials designed to test the benefits of targeting oxygen saturations from 85 to 89% versus 91 to 95% found an increase in mortality in the lower saturation group.1, 2, 3 A detailed review of the data is beyond the scope of this article,4 and there are caveats to this interpretation, but as evidence goes, this evidence appears to be remarkably strong.

Taken at face value, neonatology has answered a very simple question with an elegant set of studies. The results were compelling and somewhat surprising. The data available at the start of these trials strongly suggested that saturations of 85 to 89% would decrease severe retinopathy of prematurity (ROP) and maybe even improve respiratory outcomes, without having any impact on survival or neuro-cognitive outcomes.5, 6 With the newest results, however, it might appear that the door is closed to further questioning of the appropriate target saturations in the ELGAN. After all, multiple multi-centered, double blinded, randomized clinical trials (RCTs) pointing in the same direction are said to be the best quality evidence that clinical research has to offer. Assuming the meta-analysis7 upholds the findings of two of the three large studies, the community of neonatal practitioners will anxiously await further sub-group analysis and interpretation. But such analysis will carry the stigma of being post-hoc and thus of lesser quality than the original data.

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Authors and Affiliations

  1. Department of Pediatrics/MCHE-DPN, Brooke Army Medical Center, Houston, TX, USA

    W Lefkowitz & T C Jefferson

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  1. W Lefkowitz
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  2. T C Jefferson
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Correspondence to W Lefkowitz.

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The views expressed here are those of the authors and do not reflect the official policy or position of the Brooke Army Medical Center, the US Army Medical Department, the US Army Office of the Surgeon General, the Department of the Army, the Department of Defense or the US Government.

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Lefkowitz, W., Jefferson, T. Medicine at the limits of evidence: the fundamental limitation of the randomized clinical trial and the end of equipoise. J Perinatol 34, 249–251 (2014). https://doi.org/10.1038/jp.2013.172

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