Published online June 1, 2006
PEDIATRICS Vol. 117 No. 6 June 2006, pp. 2321-2322 (doi:10.1542/peds.2006-0566)
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Reopening the Debate on Corticosteroids: To the Editor

Caraciolo J. Fernandes, MD
Yvette R. Johnson, MD, MPH
Department of Pediatrics
Baylor College of Medicine and Texas Children's Hospital,
Houston, TX 77030

To the Editor.—

We read with interest the Doyle et al article "Low-Dose Dexamethasone Facilitates Extubation Among Chronically Ventilator-Dependent Infants: A Multicenter, International, Randomized, Controlled Trial."1 Because use of postnatal steroids in the care of premature infants has been hotly debated over the last decade, we anticipate that others, like us, will be intrigued to read the authors' comments, and some might even consider furthering their use of postnatal steroids in their practice. Although we agree with the authors that additional study is warranted, we wish to raise certain issues on this subject to refocus the questions that need be addressed as part of these investigations.

That the use of corticosteroids for ventilator-dependant infants facilitates extubation and reduces bronchopulmonary dysplasia (BPD) is not in doubt2; however, the concerns regarding the potential adverse neurodevelopmental outcomes encountered with use of postnatal steroids seem also not to be in doubt.3,4 The pervasive discussion among clinicians is whether a compromise can be achieved between the goal of early extubation to mitigate short-term outcomes and the desire not to invoke additional harm long-term.5–9 The authors have shown that a lower dose of dexamethasone than has been used previously is effective in facilitating extubation. However, the early closure of the trial and lower-than-expected sample size precludes the possibility that the key questions regarding safety will ever be answered. In this regard, we wish to redirect the emphasis of research investigations on the use of postnatal steroids toward the age-old "risk/benefit" paradigm; that is, do the benefits outweigh the risk? If so, in whom? Efficacy of postnatal steroids in facilitating extubation and preventing BPD may be logically based on the premise that small premature infants lack the capacity to synthesize adequate amounts of endogenous steroids for normal homeostasis and/or combat stress. This premise is supported by in vitro studies that suggest that the human fetal adrenal gland does not synthesize cortisol de novo until as late as 30 weeks' gestation10 and in vivo studies that link lower serum cortisol in the first week of life to the development of BPD.11 In this regard, a study by Watterberg et al12 found that early prophylactic use of hydrocortisone at 1 to 11/2 times normal basal endogenous production rates was associated with a decreased incidence of BPD. Unfortunately, a subsequent larger multicenter trial, intended to definitively confirm the findings of the pilot study, was stopped prematurely because of an increased incidence of gastrointestinal perforations in the hydrocortisone-treated infants.13 Although the larger trial did not find a difference in incidence of BPD between control and hydrocortisone-treated infants, when we consider the substantially lower final sample size (360 instead of 712) in that study, such statistically insignificant results need to be interpreted with caution in view of the increased probability of a type II error.13 What is interesting about both trials and suggests where the new frontiers for investigation for postnatal steroids lie is that infants with histologic chorioamnionitis had significantly better respiratory outcomes when treated with hydrocortisone (P < .005 to P < .04).12,13 Another interesting finding in the larger trial was the observation that those in the hydrocortisone-treated group had higher blood pressure (without an increase in hypertension),13 which, from a physiologic standpoint, would lead to improvements in ventilation-perfusion matching in the lung, decreased need for ventilator support, and earlier weaning from the ventilator. Although Doyle et al did not find any differences in blood pressure measurement during the days of treatment (P > .23), examination of their Fig 4 suggests that the blood pressure of those in the dexamethasone-treated group is higher from day 1 onward and possibly could explain the dramatic decrease in fraction of inspired oxygen (see their Fig 3)1; it is our opinion that the failure to show a difference in blood pressure between the 2 groups needs to be analyzed further and evaluated for a possible type II error. Because different steroid moieties (dexamethasone, hydrocortisone, methylprednisolone) may have differing genomic and nongenomic effects that include but are not limited to effects on inflammation, blood pressure, cytosolic calcium, etc, we propose, as noted earlier by Thebaud and Watterberg,8 that there is an urgent need for "alternatives to the present exclusive use of DXM [dexamethasone]." In view of the premise that small premature infants may be "developmentally challenged" in terms of adrenal function, studies using hydrocortisone are likely to be more appealing than those with dexamethasone.

We believe that, in clinical practice and clinical trials, one should always give consideration to the age-old axiom of the risk/benefit ratio to the patient. The studies by Watterberg et al12,13 suggest a select high-risk population of infants, who are born to women with histologic chorioamnionitis and have "relative adrenal insufficiency," for whom the benefits of using postnatal steroids may outweigh its risks.10,14 Additional research may identify other select subgroups of high-risk premature infants in whom the benefits of postnatal steroids outweigh the risks. Because trials of dexamethasone therapy have apparently fallen out of favor,1,6 it would seem prudent when studying postnatal steroids to consider alternatives to dexamethasone in populations at high risk for development of BPD. Unquestionably, given our experiences with dexamethasone, the benefits and risks of any new steroid therapy should come under intense scrutiny before any conclusions on long-term safety and efficacy can be drawn.

REFERENCES

  1. Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JB; DART Study Investigators. Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: a multicenter, international, randomized, controlled trial. Pediatrics. 2006;117 :75 –83[CrossRef][ISI][Medline]
  2. Halliday HL. Postnatal steroids and chronic lung disease in the newborn. Paediatr Respir Rev. 2004;5(suppl A) :S245 –S248[CrossRef][Medline]
  3. Barrington KJ. The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr. 2001;1 :1[Medline]
  4. O'Shea TM, Kothadia JM, Klinepeter KL, et al. 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[Abstract/Free Full Text]
  5. American Academy of Pediatrics, Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics. 2002;109 :330 –338[Abstract/Free Full Text]
  6. Doyle L, Davis P, Morley C, Blackmon LR. Effect of AAP statement regarding postnatal corticosteroids on ongoing and future randomized, controlled trials [letter]. Pediatrics. 2002;110 :1032 –1033; author reply 1032–1033[Free Full Text]
  7. Halliday HL. Early postnatal dexamethasone and cerebral palsy [commentary]. Pediatrics. 2002;109 :1168 –1169[Free Full Text]
  8. Thebaud B, Lacaze-Masmonteil T, Watterberg K. Postnatal glucocorticoids in very preterm infants: "the good, the bad, and the ugly"? Pediatrics. 2001;107 :413 –415[Free Full Text]
  9. Friedman S, Shinwell ES. Prenatal and postnatal steroid therapy and child neurodevelopment. Clin Perinatol. 2004;31 :529 –544[CrossRef][ISI][Medline]
  10. Watterberg KL. Adrenocortical function and dysfunction in the fetus and neonate. Semin Neonatol. 2004;9 :13 –21[Medline]
  11. Watterberg KL, Scott SM, Backstrom C, Gifford KL, Cook KL. Links between early adrenal function and respiratory outcome in preterm infants: airway inflammation and patent ductus arteriosus. Pediatrics. 2000;105 :320 –324[Abstract/Free Full Text]
  12. Watterberg KL, Gerdes JS, Gifford KL, Lin HM. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants. Pediatrics. 1999;104 :1258 –1263[Abstract/Free Full Text]
  13. Watterberg KL, Gerdes JS, Cole CH, et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics. 2004;114 :1649 –1657[Abstract/Free Full Text]
  14. Gordon PV. Weighing statistical certainty against ethical, clinical, and biologic expediency: the contributions of the Watterberg trial tip the scales in the right direction [letter]. Pediatrics. 2005;115 :1446 –1447; author reply 1447[Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

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Reopening the Debate on Corticosteroids: In Reply
Lex W. Doyle, Peter G. Davis, Colin J. Morley, Andy McPhee, and John B. Carlin
Pediatrics 2006 117: 2322-2323. [Extract] [Full Text]  




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