PEDIATRICS Vol. 115 No. 3 March 2005, pp. 794 (doi:10.1542/peds.2004-2203)
COMMENTARY |
Corticosteroids and Chronic Lung Disease: Time for Another Randomized, Controlled Trial?
Department of Pediatrics
University of North Carolina
Chapel Hill, NC 27599-7596
Chronic lung disease (CLD) remains one of the most challenging diseases in neonatal medicine because there have been very few effective therapies for its prevention or treatment. Systemic corticosteroids, once thought to be the "silver bullet," fell from grace because of a number of studies suggesting that the short-term benefits were outweighed by significant adverse long-term effects, namely an increased incidence of cerebral palsy (CP). However, the results of some studies were contradictory. Doyle et al1 use meta-regression analysis to review this somewhat confusing body of literature. This approach treats studies as subjects and tests the extent to which characteristics of study design contribute to variability in outcomes. The most critical characteristics in their report include the timing of treatment, the frequency of treatment of infants in the control group ("contamination"), and the incidence of CLD in the control group. Across all studies, they demonstrate no evidence of benefit (reduced mortality) and a trend toward harm (an increase in the risk of CP) among treated infants. However, they also demonstrate an inverse relationship between corticosteroid therapy and the baseline risk of CLD on the combined outcome of death or CP. The threshold of benefit based on their regression model is when the baseline risk of CLD is >50% (with the upper limit of the confidence interval of 65%).
The relationship among lung disease and its treatments, early signs of brain injury, and neurodevelopmental disability is complex and has been the subject of discussion and debate.2 Doyle et al hypothesize that, although corticosteroids have a direct toxic effect on the brain, this adverse effect may be balanced by an indirect benefit to the brain by improving lung function. We suggest an alternative or complementary explanation. The major contributor to CLD is inflammation, which may begin with uterine infection and evolve in some infants into a fetal inflammatory response.3,4 In the neonate, inflammation is exacerbated by ventilation and oxygen, which is usually confined to the lungs. However, under certain conditions, lung inflammation may be accompanied also by a systemic response.5 It is possible that high levels of proinflammatory mediators in the bloodstream, either as a result of fetal inflammation or because of the loss of compartmentalization of inflammation to the lung, may injure the brain. Corticosteroids may be beneficial in these infants, because they reduce the intensity of lung inflammation or the residua of a fetal inflammatory response and thereby decrease quantities of circulating mediators that injure the brain.
The critical question now is how the clinician should react to this very provocative publication. Let us hope that it does not provoke the widespread treatment of infants who are presumed to be at high risk for developing CLD. The findings of this study were based on investigations conducted some years ago. None of the studies reviewed used an a priori tool for determining CLD risk. None tested the relationship between baseline risk of CLD and benefit/harm of corticosteroid therapy as a primary hypothesis. As much as we all feel the need to treat or prevent what is arguably the most frustrating problem in neonatal medicine, a better alternative would be for this study to provoke the conduct of new randomized, controlled trials. Recently, given the acknowledged risks of corticosteroids, randomized, controlled trials have been difficult to justify on ethical grounds. The finding that there may be a population in which there is likely to be greater benefit than risk will permit the ethical conduct of placebo-controlled trials. The first step will be to develop a validated tool for predicting risk of CLD. This tool might include information about the inflammatory environment of the fetus and newborn. The trials should exclude the use of off-study treatment with corticosteroids. Therapies likely to confound or modify risk of CLD and CP should be standardized, and all aspects of long-term neurodevelopment should be evaluated. Only with results from trials with features such as these will the clinician be able to determine the balance between benefit and risk associated with corticosteroid therapy.
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FOOTNOTES |
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Accepted Oct 14, 2004.
Address correspondence to Carl L. Bose, MD, Division of Neonatal-Perinatal Medicine, CB#7596, University of North Carolina Hospital, Chapel Hill, NC 27599-7596. E-mail: cbose{at}med.unc.edu
No conflict of interest declared.
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics
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