Postnatal Steroids for Bronchopulmonary Dysplasia: Where Are We Now?
Article Outline
Almost 25 years ago, the first peer-reviewed publication reporting a randomized, masked trial of postnatal dexamethasone to treat bronchopulmonary dysplasia (BPD) appeared in The Lancet.1 Mammel et al treated 6 infants who had established BPD with 3 days of dexamethasone (0.5mg/gk/day) or placebo in a crossover design. The trial was stopped when sequential analysis showed significant respiratory benefit from dexamethasone, and the drug was then tapered for 1 to 4 months. Although the authors cautioned that “the therapy cannot be recommended without further study of patient selection, dosage schedules, short- and long-term side effects, and the mechanism of its action,” this and other small studies of short-term benefit led to early enthusiasm and widespread adoption of dexamethasone therapy to treat BPD.
See related articles, p 345 and 351
In a stunning application of the “more is better” theory and in contrast to accepted principles of new drug testing (start with a low dose and escalate after assessing safety), this early enthusiasm resulted in treatment with high doses of dexamethasone for as long as 6 weeks and treatment ever earlier in life. Within 5 years, infants were being enrolled in studies of dexamethasone therapy starting on the first postnatal day.2 At its most widespread use, in the late 1990s, >25% of all very low birth weight infants were exposed to postnatal steroid therapy,3 and contamination of placebo groups with open-label dexamethasone treatment became a major confounder for larger randomized trials.
Along the way, numerous cautions were sounded both by the authors of these studies and in associated commentaries, but the beneficial effect of dexamethasone on respiratory function overrode the reports of numerous short-term adverse effects such as hyperglycemia, short-term growth failure, and hypertrophic cardiomyopathy. The first convincing reports of adverse effects of high-dose dexamethasone therapy on subsequent growth and development appeared 15 years after publication of the Mammel study.4, 5 Although animal studies as early as the 1960s had consistently shown adverse effects on brain development from administration of high-dose glucocorticoids,6 the neonatology community was shocked. These new reports of long-term adverse outcomes led to a joint statement by the American Academy of Pediatrics and the Canadian Paediatric Society condemning further “routine use” of postnatal dexamethasone to treat or prevent BPD.7 Although the statement recommended additional clinical trials of dexamethasone and other glucocorticoids, the negative atmosphere made continuing enrollment in dexamethasone studies essentially impossible, ironically cutting short a randomized trial whose primary end point was neurodevelopmental outcome after a lower dose and shorter course of dexamethasone.8
Further trials of dexamethasone now appear unlikely, even in view of new information suggesting benefits in specific circumstances. First, a meta-analysis indicated that the benefits of dexamethasone in decreasing death or cerebral palsy may outweigh its risks in infants at highest risk.9 Second, in this issue of The Journal, Nixon et al report improved respiratory outcomes at 8 years of age in infants treated with dexamethasone, compared with those treated with a placebo.10 Logistic regression analysis suggested that this improvement resulted at least in part from fewer days of mechanical ventilation. Because dexamethasone facilitates extubation in infants who are chronically dependent on a ventilator,8 the benefits of a brief course of therapy in such infants could outweigh the risks.
However, dexamethasone is not the only glucocorticoid available, and the rationale for choosing it in the first place is unclear, as is the choice of an initial dose as high as that used for acute meningitis or spinal cord compression. Synthetic glucocorticoids without mineralocorticoid activity may produce deleterious effects on neurodevelopment not only by exposing the immature organism to excess glucocorticoid, but also by suppressing endogenous cortisol production, thus producing a “chemical adrenalectomy.”11 At physiologic concentrations, cortisol binds to mineralocorticoid and glucocorticoid receptors in the brain and appears to be an important regulator of neuronal function. Experimental adrenalectomy results in degeneration of neurons, specifically in the hippocampus.11 Thus, adrenal insufficiency and glucocorticoid excess can both be associated with adverse neurologic consequences.
If the aforementioned principle pertains, treatment of premature infants with lower doses of hydrocortisone should result in significantly improved neurologic outcome, compared with dexamethasone or other synthetic glucocorticoid. In this issue of The Journal, Rademaker et al report neurodevelopmental and magnetic resonance imaging outcomes at school age (7-8 years old) in a large cohort of premature infants, comparing 62 infants treated with hydrocortisone for BPD (5 mg/kg/day for 1 week, tapered for a minimum of 15 days) with 164 infants who were not treated with postnatal glucocorticoids.12 In comparison with the infants who did not receive postnatal hydrocortisone, who were larger, more mature, and less acutely ill, the infants receiving hydrocortisone had no apparent functional disadvantage or structural impairment with magnetic resonance imaging. This information is consistent with earlier reports from these authors, which showed improved outcomes for a cohort of infants treated with hydrocortisone compared with a separate cohort treated with dexamethasone.12 These findings are also consistent with information from a multicenter randomized trial, in which infants treated with early low-dose hydrocortisone (1 mg/kg/day) showed no evidence of neurodevelopmental compromise at 18 to 22 months adjusted age compared with infants who were treated with placebo.13
These studies provide an encouraging foundation for pursuing future studies of hydrocortisone therapy for BPD. As we proceed with such studies, however, let us learn from the dexamethasone experience and apply a more scientific approach. For example, as was the case for dexamethasone, the authors’ reason for choosing a particular dose of hydrocortisone was not clear. Although 5 mg/kg/day of hydrocortisone is a much lower glucocorticoid dose than 0.5 mg/kg/day of dexamethasone, it may still be higher than needed to achieve the desired effect. Data on pharmacokinetics of hydrocortisone in extremely premature infants are even more limited than information on pharmacokinetics of dexamethasone in this population.14
In the life cycle of a new therapy, early enthusiasm on the basis of small positive studies should lead to large, multicenter trials in which adverse effects are revealed and enthusiasm tempered. As the full range of a therapy’s benefits and risks become apparent through careful evaluation of these randomized, controlled studies, informed decisions can be made about the usefulness of the therapy itself. In the case of dexamethasone, the early small studies and the clinical frustration of treating infants with BPD led instead to widespread clinical use before, rather than after, large randomized trials. Thus began what now appears to be a long detour on the road of postnatal glucocorticoid therapy, with the use of an excessive dose of what may be the wrong medication at the wrong time.
So where are we now? Just as Mammel cautioned about dexamethasone in 1983, “the therapy cannot be recommended without further study of patient selection, dosage schedules, short and long-term side effects, and the mechanism of its action.”1 Clearly, the effects of glucocorticoid therapy will be a consequence of the drug, the dose, the timing, and the length of therapy. Much work remains to be done to evaluate those factors. Who to treat? When? With how much and for how long? By testing lower doses of a more appropriate medication and starting with careful evaluation of long-term outcomes from the first patients enrolled, we may be heading in a better direction.
References
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- . Early postnatal dexamethasone therapy in premature infants with severe respiratory distress syndrome: a double-blind, controlled study. J Pediatr. 1990;117:273–282
- Walsh MC, Yao Q, Horbar JD, Carpenter JH, Lee SK, Ohlsson A. Changes in the use of postnatal steroids for bronchopulmonary dysplasia in 3 large neonatal networks. Pediatrics 2006. Available at www.pediatrics.org/cgi/doi/10.1542/peds.2006-0359. Accessed February 20, 2007.
- Early dexamethasone therapy in preterm infants: a follow-up study. Pediatrics. 1998;101:E7
- Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics. 1999;104:15–21
- . Reductions in size and total DNA of cerebrum and cerebellum in adult mice after corticosterone treatment in infancy. Exp Neurol. 1968;22:191–208
- . Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics. 2002;109:330–338
- . Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: a multicenter, international, randomized, controlled trial. Pediatrics. 2006;117:75–83
- . Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease. Pediatrics. 2005;115:655–661
- . Follow-up study of a randomized controlled trial of postnatal dexamethasone therapy in very low birth weight infants: effects on pulmonary outcomes at 8 to 11 years of age. J Pediatr. 2007;150:345–350
- . The brain is an important target of adrenal steroid actions: a comparison on synthetic and natural steroids. Ann N Y Acad Sci. 1997;823:201–213
- Neonatal hydrocortisone treatment: neurodevelopmental outcome and MRI at school age in preterm born children. J Pediatr. 2007;150:351–357
- Growth and Neurodevelopmental Outcomes After Early Low-dose Hydrocortisone Treatment in Extremely Low Birth Weight Infants. Pediatrics. 2007;in press
- Watterberg KL, Shaffer ML, for the PROPHET study group. Cortisol concentrations and apparent serum half-life during hydrocortisone therapy in extremely low birth weight infants. PAS 2005;57:1501. Accessed at www.pas-meeting.org. Accessed February 20, 2007.
PII: S0022-3476(06)01201-7
doi:10.1016/j.jpeds.2006.12.041
© 2007 Mosby, Inc. All rights reserved.
Refers to article:
- Follow-up Study of a Randomized Controlled Trial of Postnatal Dexamethasone Therapy in Very Low Birth Weight Infants: Effects on Pulmonary Outcomes at Age 8 to 11 Years
- Neonatal Hydrocortisone Treatment: Neurodevelopmental Outcome and MRI at School Age in Preterm-born Children
