This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Perlman, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Perlman, J.
Related Collections
Right arrow Infectious Disease & Immunity
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

PEDIATRICS Vol. 110 No. 5 November 2002, pp. 1034

Concern About Fetus and Newborn Committee Statement on Corticosteroid Use

To the Editor.—

We read with interest the recent 2 letters to the editor and the accompanying responses and want to add our concern regarding the joint statement of the American Academy of Pediatrics Committee on Fetus and Newborn and the Canadian Paediatric Society Fetus and Newborn Committee related to the postnatal use of glucocorticoids (GCs) to ameliorate and/or prevent chronic lung disease in the very low birth weight infant.1–3 We do not argue that sustained elevations of GCs can modify both structure and function of the developing brain. Indeed, there is a large body of experimental evidence describing adverse consequences, including a reduction in regional cerebral blood flow specifically to the hippocampus with concomitant histologic changes noted in CA1 and CA3 cell fields, a significant reduction in hippocampal volume, a downregulation of myelin basic protein and proteolipid protein in white matter, delayed myelination of optic axons, hyperactivity of the hypothalamic-pituitary-adrenal axis, and alterations in dopamine receptor responses.4–11 However, these changes are not always persistent. Thus, the downregulation of white matter proteins corrected after the discontinuation of the steroids.5 We do not disagree that the meta-analysis as presented suggests worse neurodevelopmental outcome after GC exposure. However, we concur with the criticism of both Dunn et al and Jacobs et al of the analysis, and in addition have concerns regarding interpretation of the neurologic outcome. As one example, the study by O’Shea et al12 reported an increased incidence of cerebral palsy but no difference on the Mental Developmental Index or Psychomotor Developmental Index. In discussing this discordancy, O’Shea states "80% of study infants had either spastic diplegia or hemiplegia . . . children with this form of cerebral palsy have mild rather than severe developmental delay." Two comments; first, it is difficult to reconcile a mechanism whereby dexamethasone would produce an asymmetric lesion resulting in a hemiplegia, and second, as pointed out by Pinto-Martin et al,13 the most common cause of nondisabling cerebral palsy is spastic diplegia that often is related to prenatal rather than postnatal factors.

We consider it critical that any discussion of chronic lung disease (CLD), its treatment, and neurologic outcome should provide a measure of severity of the underlying lung disease (this description is invariably lacking in the rescue studies presented in the meta-analysis). Thus, for example, bronchopulmonary dysplasia (BPD) was categorized into 4 stages by Northway14; each stage had a distinctive histopathologic correlation. The relevance of this relates to the observations that the severe forms of BPD are associated with increased mortality (including an increased risk for sudden infant death syndrome) and long-term morbidity including neurologic morbidity.15,16 Indeed, Northway16 reported a 34% incidence of significant neurologic deficits in survivors of BPD including cerebral palsy, mental retardation, blindness, and deafness. Subsequent reports have also demonstrated significant neurologic abnormalities with severe BPD including poor head growth, progressive neurologic deterioration, a movement disorder, and (at autopsy) evidence of global neuronal loss; all this is described before the use of GCs for CLD.16,17–25

The pulmonary substrate for CLD of prematurity, the predominant form of disease in the 1990s, remains poorly defined histologically, but seems to be primarily inflammatory-mediated.26,27 The condition may or may not have hyaline membrane disease as the precipitating factor. Irrespective of initial ventilator requirement or management as well as other strategies such as vitamin A administration, careful fluid management, etc, the disease seems to progress between the second and fourth weeks of postnatal age in a substantial number of infants.28 Interestingly, there seems to be a strong association with chorioamnionitis; in particular, when there is associated funisitis.29,30 Chorioamnionitis is also associated with an increased risk for cerebral palsy.31

The American Academy of Pediatrics recommendation number 5 states "Outside the context of a randomized, controlled trial, the use of corticosteroids should be limited to exceptional clinical circumstances (eg, an infant on maximal ventilatory and oxygen support). In those circumstances parents should be fully informed about the known short- and long-term risks and agree to treatment." This statement places the clinician in a vulnerable position both medically as well as legally for several reasons. First, what does maximum ventilatory and oxygen support imply? Indeed, whatever its intended goal, it may be too late for GCs to be effective. Second, this statement, as well as several recent reports on the subject, fails to present the body of clinical evidence (as noted above) indicating that severe lung disease in and of itself is associated with significant neurologic morbidity.3,32 This information has to be incorporated into discussions with the family if they are to be "fully informed."

Several important questions remain unanswered with regard to GC use in a preterm infant with progressive lung disease. They include 1) when should GCs be considered a viable treatment option, 2) what dose should be administered, and 3) what duration of therapy should be used. We would suggest that if after approximately 2 to 3 weeks there is clinical and radiologic evidence of progressive pulmonary disease despite optimal ventilatory and supportive therapy, then therapy should be considered with the desired goal of facilitating extubation. It is our contention that prolonged intubation is stressful and may have indirect adverse cerebral effects via release of endogenous steroids.33 Recent evidence suggests that a lower dose may be equally effective and that a short duration, ie, 7 to 14 days, may achieve desired goals.34

Jeffrey Perlman, MB
UT Southwestern Medical Center
Department of Pediatrics
Dallas, TX 75390-9063

REFERENCES

  1. American Academy of Pediatrics, Committee on Fetus and Newborn and Canadian Paediatric Society, Fetus and Newborn Committee. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics.2002; 109 :330 –338[Abstract/Free Full Text]
  2. Taylor C, Shah PS, Dunn MS. Meta-analysis of postnatal steroid use challenged. Pediatrics.2002; 109 :716 –717[Free Full Text]
  3. Jacobs HC, Chapman RL, Gross I. Premature conclusions on postnatal steroid effects. Pediatrics.2002; 110 :200 –201[Free Full Text]
  4. Endo Y, Nishimura JI, Kobayashi S, et al. Long-term glucocorticoid treatments decrease cerebral blood flow in the rat hippocampus in association with histological damage. Neuroscience.1997; 79 :745 –752[CrossRef][Web of Science][Medline]
  5. Tsuneishi S, Takada S, Toshiyuki M, et al. Effects of dexamethasone on the expression of myelin basic protein, proteolipid protein and glial fibrillary acidic protein genes in developing brain. Dev Brain Res.1991; 61 :117 –123[CrossRef][Medline]
  6. Dunlop SA, Archer MA, Quinlivan JA, Beazley LD, Newnham JP. Repeated prenatal corticosteroids delay myelination in the ovine central nervous system. J Matern Fetal Med.1997; 6 :309 –313[CrossRef][Medline]
  7. Diaz R, Fuxe K, Ogren SO. Prenatal corticosterone treatment induces long-term changes in spontaneous and apomorphine mediated motor activity in male and female rats. Neuroscience.1997; 81 :129 –140[CrossRef][Web of Science][Medline]
  8. Chen J, Adachi N, Tsubota S, Nagoro T, Arai T. Dexamethasone augments ischemia-induced extracellular accumulation of glutamate in gerbil hippocampus. Euro J Pharm.1998; 347 :67 –70
  9. Horner HC, Packan DR, Sapolsky RM. Glucocorticoids inhibit glucose transport in cultured hippocampal neurons and glial. Neuroendocrinology.1990; 52 :57 –64[Web of Science][Medline]
  10. Behl C, Lezoualch F, Trapp T, et al. Glucocorticoids enhance oxidative stress-induced cell death in hippocampal neurons in vitro. Endocrinology.1997; 138 :101 –106[Abstract/Free Full Text]
  11. McIntosh LJ, Sapolsky RM. Glucocortcoids increase the accumulation of reactive oxygen species and enhance adriamycin-induced toxicity in neuronal culture. Exp Neurol.1996; 141 :201 –206[CrossRef][Web of Science][Medline]
  12. 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]
  13. Pinto-Martin JA, Riolo S, Cnaan A, Holzman C, Susser MW, Paneth N. Cranial ultrasound prediction of disabling and nondisabling cerebral palsy at age two in a low birth weight population. Pediatrics.1995; 95 :249 –254[Abstract/Free Full Text]
  14. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline membrane disease. N Engl J Med.1967; 276 :357 –368
  15. Abman SH, Burchell MF, Schaffer MS, Rosenberg AA. Late sudden unexpected deaths in hospitalized infants with bronchopulmonary dysplasia. Am J Dis Child.1989; 143 :815 –819[Abstract/Free Full Text]
  16. Northway WH Jr. Observations on bronchopulmonary dysplasia. J Pediatr.1979; 95 :815 –817[CrossRef][Web of Science][Medline]
  17. Vohr BR, Bell EF, Oh W. Infants with bronchopulmonary dysplasia. Am J Dis Child.1982; 136 :443 –447[Abstract/Free Full Text]
  18. Mayes L, Perke HE, Stahlman MT. Severe bronchopulmonary dysplasia. Acta Paediatr Scand.1983; 72 :225 –229[Web of Science][Medline]
  19. Lipschitz MH, Seilheimer DK, Wilson GS, et al. Neurodevelopmental status of low birthweight infants with bronchopulmonary dysplasia requiring prolonged oxygen supplementation. J Perinatol.1985; 7 :127 –132
  20. Yu VH, Orgill AA, Bajuk SBL, Astbury J. Growth and development of very low birthweight infants recovering from bronchopulmonary dysplasia. Arch Dis Child.1983; 58 :791 –794[Abstract/Free Full Text]
  21. Shankaran S, Szego E, Eizert D, Siegel P. Severe bronchopulmonary dysplasia. Predictors of survival and outcome. Chest.1984; 86 :607 –610[Abstract/Free Full Text]
  22. Ellison PH, Farina MA. Progressive central nervous system deterioration: a complication of advanced chronic lung disease of prematurity. Ann Neurol.1980; 8 :43[CrossRef][Web of Science][Medline]
  23. Campbell LR, McAlister W, Volpe JJ. Neurologic aspects of bronchopulmonary dysplasia. Clin Pediatr.1998; 27 :7 –13
  24. Smith JF, Reynolds EOR, Taghizadeh A. Brain maturation and damage in infants dying from chronic pulmonary insufficiency in the postneonatal period. Arch Dis Child.1974; 49 :359 –365[Abstract/Free Full Text]
  25. Perlman JM, Volpe JJ. Movement disorder of premature infants with severe bronchopulmonary dysplasia: a new syndrome. Pediatrics.1989; 84 :215 –218[Abstract/Free Full Text]
  26. Ozdemir A, Brown MA, Morgan WJ. Markers and mediators of inflammation in neonatal lung disease. Pediatr Pulmonol.1997; 23 :292 –306[CrossRef][Web of Science][Medline]
  27. Speer CP. New insights into the pathogenesis of pulmonary inflammation in preterm infants. Biol Neonate.2001; 79 :205 –209[CrossRef][Web of Science][Medline]
  28. Lemons JA, Bauer CR, Oh W, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1995 through December 1996. Pediatrics.2001; 107(1) . Available at: http://www.pediatrics.org/content/full/107/1/e1
  29. Van Marter LJ, Dammann O, Allred EN, et al. Chorioamnionitis, mechanical ventilation and postnatal sepsis as modulators of chronic lung disease in preterm infants. J Pediatr.2002; 140 :171 –176[CrossRef][Web of Science][Medline]
  30. Matsuda T, Nakajima T, Hattori S, et al. Necrotizing funisitis: clinical significance and association with chronic lung disease in premature infants. Am J Obstet Gynecol.1997; 177 :1402 –1407[CrossRef][Web of Science][Medline]
  31. Wu YW. Chorioamnionitis as a risk factor for cerebral palsy. JAMA.2000; 282 :1417 –1424[Free Full Text]
  32. Murphy BP, Inder TE, Huppi PS, et al. Impaired cerebral cortical gray matter growth after treatment with dexamethasone for neonatal chronic lung disease. Pediatrics.2001; 107 :217 –221[Abstract/Free Full Text]
  33. Perlman JM. Neurobehavioral deficits in premature graduates of intensive care—potential medical and environmental risk factors. Pediatrics.2001; 108 :1339 –1348[Abstract/Free Full Text]
  34. Durand M, Mendoza ME, Tantivit P, Kugelman A, McEvoy C. A randomized trial of moderately early low-dose dexamethasone therapy in very low birthweight infants: dynamic pulmonary mechanics, oxygenation, and ventilation. Pediatrics.2002; 109 :262 –268[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
L. B. Clerch, A. S. Baras, G. D. Massaro, E. P. Hoffman, and D. Massaro
DNA microarray analysis of neonatal mouse lung connects regulation of KDR with dexamethasone-induced inhibition of alveolar formation
Am J Physiol Lung Cell Mol Physiol, February 1, 2004; 286(2): L411 - L419.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Perlman, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Perlman, J.
Related Collections
Right arrow Infectious Disease & Immunity
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?