PEDIATRICS Vol. 105 No. 3 March 2000, pp. 542-548

Early DexamethasoneAttempting To Prevent Chronic Lung Disease

Robert A. Sinkin, MD^*, Harry S. Dweck, MD^, , Michael J. Horgan, MD^§, Keith J. Gallaher, MD, Christopher Cox, PhD^*, William M. Maniscalco, MD^*, Patricia R. Chess, MD^*, Carl T. D'Angio, MD^*, Ronnie Guillet, MD, PhD^*, James W. Kendig, MD^*, Rita M. Ryan, MD^*, and Dale L. Phelps, MD^*

From the Departments of Pediatrics (Neonatology) and Biostatistics, ^* Children's Hospital at Strong, Rochester, New York;  Westchester Medical Center, Valhalla, New York; ^§ Albany Medical College, Albany, New York;  Cape Fear Valley Medical Center, Fayetteville, North Carolina.

	ABSTRACT

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Background.  We previously demonstrated improved survival and early outcomes in a pilot trial of 2 doses of intravenous dexamethasone for infants with surfactant-treated respiratory distress syndrome.¹ A multicenter, randomized, double-blind trial was undertaken to confirm these results.

Methods.  Infants <30 weeks' gestation were eligible if they had respiratory distress syndrome, required mechanical ventilation at 12 to 18 hours of age, and had received at least 1 dose of exogenous surfactant. Infants were excluded if sepsis or pneumonia was suspected or if congenital heart disease or chromosomal abnormalities were present. A total of 384 infants were enrolled189 randomized to dexamethasone (.5mg/kg birth weight at 12-18 hours of age and a second dose 12 hours later) and 195 to an equal volume of saline placebo.

Results.  No differences were found in the dexamethasone versus placebo groups, respectively, regarding the primary outcomes of survival (79% vs 83%), survival without oxygen at 36 weeks' corrected gestational age (CGA; both 59%), and survival without oxygen at 36 weeks' CGA and without late glucocorticoid therapy (46% vs 44%). No significant differences between the groups in estimates from Kaplan-Meier survival analyses were found for median days on oxygen (50 vs 56 days), ventilation (20 vs 27 days), days to regain birth weight (15.5 vs 14 days), or length of stay (LOS; 88 vs 89 days). Infants given early dexamethasone were less likely to receive later glucocorticoid therapy for bronchopulmonary dysplasia during their hospitalization (27% vs 35%). No clinically significant side effects were noted in the dexamethasone group, although there were transient elevations in blood glucose and blood pressure followed by a return to baseline by study day 10. Among infants who died (40 vs 33), there were no differences in the median days on oxygen, ventilation, nor LOS. However, in survivors (149 vs 162), the following were observed: median days on oxygen 37 versus 45 days, ventilation 14 versus 19 days, and LOS 79 versus 81 days, for the dexamethasone versus placebo groups, respectively.

Conclusions.  This dose of early intravenous dexamethasone did not reduce the requirement for oxygen at 36 weeks' CGA and survival was not improved. However, early dexamethasone reduced the use of later prolonged dexamethasone therapy, and among survivors, reduced the median days on oxygen and ventilation. We conclude that this course of early dexamethasone probably represents a near minimum dose for instituting a prophylactic regimen against bronchopulmonary dys- plasia.  Key words:  neonate, bronchopulmonary dysplasia, glucocorticoids, randomized clinical trials, respiratory distress syndrome.

Bronchopulmonary dysplasia (BPD) is a form of emphysematous chronic lung disease (CLD) that is a significant complication of current neonatal intensive care and a leading cause of neonatal morbidity and mortality during the first year of life. BPD is associated with varying degrees of fibrosis that can develop over days to weeks after a variety of respiratory insults in the newborn infant.² The cellular basis of lung injury encountered in BPD is an area of intense investigation. An inflammatory response to a pulmonary insult is implicated in the pathogenesis of BPD and, specifically, the secretory products of the pulmonary alveolar macrophage and the polymorphonuclear leukocyte.^3-10

Multiple studies have shown glucocorticoid therapy to be effective in established BPD. Intravenous dexamethasone has been used in differing regimens and in chronologically younger patients.^11-16 Some investigators have focused on the use of early dexamethasone to prevent the establishment of CLD.^117-23 The potential for serious sequelae from the use of glucocorticoid therapy in premature infants remains a concern.^11,1424-29 A pilot study conducted at the University of Rochester Medical Center investigated the use of early intravenous dexamethasone in surfactant-treated premature infants with respiratory distress syndrome (RDS).¹ The course of dexamethasone was limited to 2 doses (at 12-18 hours with a second dose 12 hours later). The treatment group required less ventilatory support and supplemental oxygen after 4 days of age. The treatment group also had shorter hospitalizations. Survival in the treatment group was 89% versus 67% in the placebo group (P = .08), whereas survival without BPD was 67% versus 43% (P = .14) in the 2 groups, respectively. No differences in adverse sequelae were seen.

The results of this phase 1 study to test the efficacy and safety of 2 early doses of dexamethasone suggested that such administration in a defined, high-risk population improves short-term pulmonary function and may have long-term benefits including improved survival. The lack of significant increases in adverse effects was encouraging. As a result, a larger, multicenter, randomized trial was conducted to further assess clinical efficacy and safety of this treatment strategy.

	METHODS

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This study was performed at the Children's Hospital at Strong, Rochester, NY; Westchester Medical Center, Valhalla, NY; Albany Medical College, Albany, NY; and Cape Fear Valley Medical Center, Fayetteville, NC, from March 1992 through February 1997. The study was approved by the research subjects review boards at all 4 centers and informed consent was obtained from the parents of the infants.

Patient Population

Infants <30 weeks' gestation were eligible if they had RDS diagnosed by clinical and radiographic signs, required mechanical ventilation at 12 to 18 hours of age, and had received at least 1 dose of exogenous surfactant. The purpose for requiring exogenous surfactant replacement therapy for study eligibility was to maintain as uniform a study population as possible. All infants were eligible to receive subsequent doses of exogenous surfactant if they continued to require mechanical ventilation with a mean airway pressure 7 mm Hg or an fraction of inspired oxygen requirement (FIO₂ ) .4, or both. Prophylactic surfactant therapy (administration of surfactant within 10 minutes of age³⁰) was used for inborn neonates <29 weeks' gestation. In those infants, classic radiographic findings of RDS may not have been present, so that a clinical course consistent with RDS was used, including the need for a second surfactant dose. Exclusion criteria at entry included a strong suspicion of sepsis or pneumonia (ie, chest radiograph findings not consistent with RDS, cardiovascular instability, neutropenia, and severe maternal chorioamnionitis), congenital heart disease, and chromosomal abnormalities.

Randomization/Intervention

After identification of eligible infants and informed consent, infants were randomized with stratification by center from a set of sealed envelopes in the pharmacy. Syringes labeled dexamethasone study drug were sent to the nursery containing either the appropriate dose of dexamethasone (.5 mg/kg birth weight) or normal saline placebo, with the first dose administered between 12 and 18 hours of age and the second dose 12 hours later. Investigators and caretakers were blinded to the study drug. All other aspects of care were according to the standard practice of the neonatal intensive care units at their respective hospitals, including the later use of dexamethasone for CLD. Use of later dexamethasone therapy was at the discretion of the attending neonatologist at each unit. In general, this therapy was reserved for ventilator dependent neonates who were requiring an FIO₂ >.30 and failing to wean from the ventilator beyond 10 days of age.

Short-Term Clinical Outcome Variables

Short-term clinical outcome variables were obtained on 1 through 7 and 10 days of age and included weight, mean blood pressure, mean blood glucose, complete blood counts with differential, need for insulin or antihypertensive therapies, need for pharmacologic blood pressure support, and degree of ventilatory support. The latter included results of blood gas analysis (pH and blood gas tension values) and ventilator settings including peak inspiratory, positive end expiratory and mean airway pressures, rate, and FIO₂. The complications of incidences of sepsis, necrotizing enterocolitis (NEC) and isolated gastrointestinal perforation were tracked, each of which has been attributed to glucocorticoid therapy.

Longer-Term Clinical Outcome Variables

Longer-term clinical outcome variables (outcomes of hospitalization) included survival, age at extubation, days on the ventilator, days requiring supplemental oxygen, days to regain birth weight, the presence and severity of intraventricular hemorrhage, need for home oxygen and medications (ie, diuretics, bronchodilators, methylxanthines), and total number of hospital days. An oxygen requirement at 28 days and at 36 weeks' corrected gestational age (CGA)³¹ and use of additional corticosteroid therapy were also evaluated.

Statistical Analysis

Sample Size In our pilot study, oxygen-free survival to 36 weeks' CGA increased from 43% in controls to 68% in the treated group. For the multicenter trial, a sample was determined that would give 80% power to detect a difference of at least 15 percentage points between the 2 groups. We reasoned that because over time, the actual incidence of oxygen-free survival at 36 weeks' CGA may be higher in the control group, this would be a desirable and clinically meaningful difference. With a significance level of .05, 186 infants in each arm of the study would conservatively satisfy these estimates.

	RESULTS

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Patient Population

During the study period, a total of 973 infants <30 weeks' gestation were admitted to the 4 centers. Of these, 140 did not meet entry criteria, 65 expired before enrollment or were moribund, 129 were excluded attributable to presumed sepsis, 48 were not enrolled because of refused parental consent, 149 missed enrollment, and 58 were not enrolled because of other miscellaneous reasons. A total of 384 infants were enrolled during the study period with 195 randomized to the placebo group and 189 randomized to the dexamethasone group. Among the enrolled infants, no differences were seen between the 2 groups with respect to birth weight, gestational age, gender, race, 1- and 5-minute Apgar scores (Table 1). Likewise, there were no differences in antepartum factors including maternal white blood cell count (16.0 ± .4 × 10³/mm³), percentage of mothers with positive cervical culture (18%), or incidence of chorioamnionitis (30%).

No clinically significant differences were seen between the 2 groups at entry with respect to pulmonary baseline characteristics: degree of ventilatory and oxygen support (similar peak inspiratory, end expiratory and mean airway pressures, mandatory ventilatory rates, and FIO₂); white blood cell counts (11.2 ± .6 × 10³/mm³); blood gas results (arterial partial pressure of oxygen and arterial partial pressure of carbon dioxide, 75 ± 2 mm Hg and 36 ± 1 mm Hg, respectively); serum glucose (114 ± 5 mg%); mean blood pressure (34 ± .5 mm Hg). Five infants in both groups were found to have positive admission blood culture results.

Pulmonary Status

The goal of the ventilatory strategy used was to maintain the arterial partial pressure of oxygen between 6.7 and 9.3 kPa (50 and 70 mm Hg) and the arterial partial pressure of carbon dioxide between 6.0 and 7.3 kPa (45 and 55 mm Hg). Figures 1 and 2 display the mean airway pressure and FIO₂, respectively, over time in the dexamethasone and placebo groups. These data were analyzed using 2-way repeated measures of analysis of variance. This analysis includes a Test of Interaction in which the null hypothesis states that the 2 curves are parallel over time. A significant result indicates that the 2 curves are not parallel, and therefore, that differences between the 2 groups change over time (and in particular, are not all zero). The nature of these differences can be seen in those There was a significant lowering of mean airway pressure in the dexamethasone group (P = .02 for the test of interaction indicating a significant change in the difference between the 2 groups over time) with the largest differences occurring after day 3. Similar statistically significant findings were also seen for peak inspiratory pressure, positive end-expiratory pressure, and intermittent mandatory ventilation (data not shown). However, FIO₂ did not differ significantly between the 2 groups during the initial 10 days. Blood gas analyses revealed no significant differences between the 2 groups during the same period (data not shown).

View larger version (17K): [in this window] [in a new window]   Fig. 1.   Mean airway pressure over time, by treatment group. y-axis = mean airway pressure (cm H2O); x-axis = age in days. All values are means with standard error (SE) bars.

View larger version (14K): [in this window] [in a new window]   Fig. 2.   Mean FIO2 over time, by treatment group. y-axis = FIO2; x-axis = age in days. All values are means with SE bars.

Outcomes of Hospitalization

Early intravenous dexamethasone did not lessen the requirement for oxygen at 36 weeks' CGA, and survival was not improved. Survival without an oxygen requirement at 28 days or at 36 weeks' CGA, likewise, did not differ between the 2 groups (Table 2). Survival in the dexamethasone group was 79% versus 83% in the placebo group (P = .29). Survival analysis using proportional hazard regression with adjustment for study center produced similar results for days of mechanical ventilation, supplemental oxygen, and hospitalization with no differences found between the 2 treatment groups (Table 2). However, significantly fewer patients in the dexamethasone group received an additional course of glucocorticoid therapy for lung disease than did those in the placebo group (27% vs 37%, respectively; P = .04). There were no center differences in the use of later glucocorticoid therapy. The mean age of administration for later dexamethasone was 22 days (range: 7-87 days) in the early dexamethasone group and 21 days (range: 3-55 days) in the placebo group.

A secondary analysis failed to show any differences between those infants who died in the 2 groups. Therefore, further characterization of the survivors was performed. As shown in Table 3, there was a significant reduction in median days of mechanical ventilation and of supplemental oxygen in the dexamethasone treated group. A lowering of 11% in the dexamethasone group in the percent of infants requiring greater than 1 dose of surfactant approached significance between the 2 groups (P = .05).

Complications

No significant differences between the 2 groups were seen with respect to the incidence or severity of intraventricular hemorrhage, the need for insulin therapy, the need for antihypertensives, the number of positive blood culture results, or the number of days to regain birth weight (Table 4). There were elevations in mean blood pressure (Fig 3) and mean blood glucose (Fig 4) in the dexamethasone group (P = .09 and P = .0003, respectively) over time, although these were not clinically significant. Mean blood pressure was elevated on study days 4 through 7 in the dexamethasone group. This difference, however, resolved by study day 10 without pharmacologic intervention. No significant differences between the 2 groups were seen with respect to NEC, isolated intestinal perforation, retinopathy of prematurity, air leak (ie, pneumothorax or pulmonary interstitial emphysema), or the need for home oxygen. A significantly fewer number of infants in the dexamethasone group were discharged to home on medications (13% vs 25%; P = .008; Table 4).

View larger version (15K): [in this window] [in a new window]   Fig. 3.   Mean cuff blood pressure over time, by treatment group. y-axis = mean blood pressure (mm Hg); x-axis = age in days. All values are means with SE bars.

View larger version (17K): [in this window] [in a new window]   Fig. 4.   Mean serum blood glucose over time, by treatment group. y-axis = mean whole blood glucose (mg %); x-axis = age in days. All values are means with SE bars.

	DISCUSSION

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Dexamethasone is widely used for the treatment of established CLD.^14,1532-37 Although glucocorticoid therapy has side effects, some of which are serious, they are usually considered justified in light of the demonstrated improvement in pulmonary function.^11,1424-29 The early use of glucocorticoid therapy in an infant's neonatal intensive care unit admission has also been tested.^{12,13,1638-40} We and others evaluated the efficacy of early glucocorticoid therapy in preventing CLD.^{1,18,1921-2341-45} Because the inflammatory response in infants with RDS may contribute to developing BPD, we reasoned that CLD may be mitigated by early glucocorticoid therapy.^4,10,4446-48 Another possible mechanism for an early beneficial effect is supplementation of corticosteroids to infants with inadequate adrenal responsiveness, which would make them more vulnerable to inflammatory lung injury. Watterberg and Scott⁴⁹ demonstrated a blunted response to adrenocorticotropic hormone challenge on days 5 to 7 in low birth weight newborns who develop BPD, supporting their hypothesis that BPD resulted in part from a poorly controlled inflammatory response caused by decreased endogenous cortisol secretion.

A few recent reviews summarize many of the varying studies on the safety and efficacy of corticosteroid therapy.^50,51 Differing patient populations (both gestational age and chronologic age at which glucocorticoid therapy is initiated), use and type of surfactant, and differing corticosteroid dosing schedules make comparisons among these studies difficult. For example, the study by Shinwell et al,⁴² which used a 3-day dexamethasone treatment strategy beginning at 12 hours of age, failed to demonstrate a decrease in CLD or an improvement in survival. However, their study population differed significantly from ours and that of Garland et al.²² The 18-center Israeli study enrolled 248 neonates, none of whom were given prophylactic surfactant, with a 300-g higher mean birth weight (~1180 g) and an average gestational age of 29 weeks. By comparison, our study population had a mean birth weight of ~875 g and an average gestational age of 26 weeks. Also, 36% of their patients had complete or partial prenatal corticosteroid therapy, whereas nearly 56% of our patients were exposed to this therapy.

A recent meta-analysis reviewed published trials on the use of early dexamethasone (within 14 days of birth) to measure efficacy in reducing the incidence of CLD and the incidence of clinically significant side effects.⁵² The results suggest a significant reduction in the risk of CLD at 28 days and 36 weeks' CGA. Transient hypertension, hyperglycemia, and an increase in the number of days to regain birth weight were the side effects found.⁵² Another meta-analysis demonstrated similar benefits in promoting early extubation, decreased risks of CLD at 28 days and 36 weeks' CGA and an almost significant reduction in risk of pulmonary air leak and in death or CLD at 36 weeks' CGA.⁵³ However, the authors cautioned that the potential adverse effects, including gastrointestinal bleeding, hypertension, and hyperglycemia, may outweigh the benefits.

Our results are consistent with the positive findings on pulmonary status as previously reported.^11,1424-29 We did not find the adverse effects of elevated blood pressure or glucose levels to be clinically significant and there was not any difference detected in the incidence of NEC or isolated bowel perforation. We did not collect data on gastrointestinal hemorrhage. We found that the use of a very short course of dexamethasone in the very early stages of RDS to be efficacious in reducing the need for later prolonged dexamethasone therapy (P = .04), which is associated with a higher likelihood of complications. Early dexamethasone had a beneficial effect on infants who survived: the median days on oxygen (P = .016) and median days ventilated (P = .018) were lower and the number of subsequent surfactant doses were reduced. These factors may reduce hospitalization costs.

Dexamethasone, however, is a potent agent. Although the short-term side effects are mostly transient,^1,45 the long-term side effects of early dexamethasone need additional study. Yeh et al⁵⁴ report concerns with adverse effects of early dexamethasone on neuromotor function and somatic growth at 2 years old. The first dose of dexamethasone in that study was given within 12 hours of birth; however, the dosing regimen was 28 days in length, resulting in a total dexamethasone dose 6 times the total dose used in our study. Gilmour et al⁵⁵ evaluated growth and body composition at term of infants <1500 g at birth who were given pulse dexamethasone therapy (3 days of dexamethasone therapy beginning at a week of age and repeated weekly while the neonate was ventilated or receiving supplemental oxygen or until 36 weeks' CGA).¹³ Although short-lived effects on growth were demonstrated, by 36 weeks' CGA, no effect was demonstrable. A longer term follow-up evaluation is planned. O'Shea et al⁵⁶ recently reported an association of later dexamethasone therapy with an increased risk of cerebral palsy at 1-year adjusted age, cautioning that glucocorticoid therapy should be reserved for those neonates at risk for severe CLD.

The optimal dosing strategy of dexamethasone remains to be determined. Although our early 2-dose protocol lowered the rate of some BPD indicators, 32% of the survivors in the early dexamethasone group still received late glucocorticoid therapy for BPD. An alternative early dosing schedule might reduce this percentage. Also, the use of later glucocorticoid therapy for BPD in both groups likely reduced the magnitude of the differences between the groups by rescuing the larger number of BPD infants in the placebo group. These findings are similar to those of several recently published studies. Kovacs et al²³ compared 3 days of dexamethasone followed by nebulized budesonide for 18 days versus placebo and found a decreased administration of later dexamethasone rescue for BPD (23.3% vs 56.7%; P = .02). Cole et al²¹ also showed lower systemic glucocorticoid administration in neonates treated with inhaled beclomethasone versus placebo. Both of these studies failed to demonstrate a lowered incidence of CLD at 36 weeks²³ or of BPD at 28 days.²¹ Garland et al²² found that a 3-day course of dexamethasone starting at 24 to 48 hours of age increased survival without CLD, reduced CLD, and reduced late dexamethasone therapy. The cumulative dosage used in that study was initially 1.35 mg/kg but then lowered to 1.175 mg/kg when a higher incidence of gastrointestinal perforation was noted in the treatment group compared with the placebo arm. Perhaps our shortened treatment regimen and lower cumulative dexamethasone (1mg/kg) is responsible for our lower incidence of gastrointestinal perforation. However, other significant differences in study design exist between these 2 studies and make additional comparisons difficult.

	CONCLUSION

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We conclude that the course of early dexamethasone in this report did not reduce the requirement for oxygen at 36 weeks' CGA, and survival was not improved. However, our regimen of early dexamethasone reduced the use of later prolonged dexamethasone therapy, and among survivors, reduced the median days on oxygen and ventilation. This course of early dexamethasone is safe and probably represents a near minimum dose for instituting a prophylactic regimen against BPD. Additional study is necessary to find the optimal dosing schedule in neonates, perhaps focusing on those predicted to be at high risk for developing CLD.

	ACKNOWLEDGMENTS

This work was supported by Pulmonary SCOR Grant HL-36543 from the National Institutes of Health, General Clinical Research Center Grant 5 MO1 RR00044, and clinical research Grant 6-0785 from the March of Dimes.

We thank Linda Reubens, RN, for her untiring efforts in serving as study center coordinator and for data collection and verification and Arthur Watts for data processing. This study could not have been completed without the dedication and cooperation of all the neonatal intensive care unit nurses and families.

	FOOTNOTES

Deceased.

We dedicate this manuscript to Harry Dweck, MD.

Received for publication Feb 16, 1999; accepted Jul 20, 1999.

This work was presented at the meeting of the Pediatric Academic Societies; May 4, 1998; New Orleans, LA.

Reprint requests to (R.A.S.) Department of Pediatrics (Neonatology), Children's Hospital at Strong, University of Rochester Medical Center, 601 Elmwood Ave, Box 651, Rochester, NY 14642. E-mail: robert_sinkin{at}urmc.rochester.edu

	ABBREVIATIONS

BPD, bronchopulmonary dysplasia; CLD, chronic lung disease; RDS, respiratory distress syndrome; FIO₂, fraction of inspired oxygen; NEC, necrotizing enterocolitis; CGA, corrected gestational age; SE, standard error; LOS, length of stay.

	REFERENCES

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1. Sanders RJ, Cox C, Phelps DL, Sinkin RA Two doses of early intravenous dexamethasone for the prevention of bronchopulmonary dysplasia in babies with respiratory distress syndrome. Pediatr Res 1994; 36:122-128 [Medline]
2. Northway WH Jr, Rosan RC, Porter DY Pulmonary disease following respirator therapy of hyaline-membrane disease: bronchopulmonary dysplasia. N Engl J Med 1967; 276:357-368
3. Watterberg KL, Demers LM, Scott SM, Murphy S Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996; 97:210-215 [Abstract/Free Full Text]
4. Bagchi A, Viscardi RM, Taciak V, Ensor JE, McCrea KA, Hasday JD Increased activity of interleukin-6 but not tumor necrosis factor-alpha in lung lavage of premature infants is associated with the development of bronchopulmonary dysplasia. Pediatr Res 1994; 36:244-252 [Medline]
5. Doshi N, Kanbour A, Fujikura T, Klionsky B Tracheal aspiration cytology in neonates with respiratory distress: histopathologic correlation. Acta Cytol 1982; 26:15-21 [Medline]
6. LoMonaco MB, Barber CM, Sinkin RA Differential cytokine mRNA expression by neonatal pulmonary cells. Pediatr Res 1996; 39:248-252 [Medline]
7. Merritt TA, Puccia JM, Stuard ID Cytologic evaluation of pulmonary effluent in neonates with respiratory distress syndrome and bronchopulmonary dysplasia. Acta Cytol 1981; 25:631-639 [Medline]
8. Merritt TA, Stuard ID, Puccia J, Newborn tracheal aspirate cytology: classification during respiratory distress syndrome and bronchopulmonary dysplasia. J Pediatr 1981; 98:949-956 [CrossRef][Medline]
9. Ogden BE, Murphy S, Saunders GC, Johnson JD Lung lavage of newborns with respiratory distress syndrome: prolonged neutrophil influx is associated with bronchopulmonary dysplasia. Chest 1983; 83:31S-33S [Free Full Text]
10. Ogden BE, Murphy SA, Saunders GC, Pathak D, Johnson JD Neonatal lung neutrophils and elastase/proteinase inhibitor imbalance. Am Rev Respir Dis 1984; 130:817-821 [Medline]
11. Avery GB, Fletcher AB, Kaplan M, Brudno DS Controlled trial of dexamethasone in respirator-dependent infants with bronchopulmonary dysplasia. Pediatrics 1985; 75:106-111 [Abstract/Free Full Text]
12. Cummings JJ, D'Eugenio DB, Gross SJ A controlled trial of dexamethasone in preterm infants at high risk for bronchopulmonary dysplasia. N Engl J Med 1989; 320:1505-1510 [Abstract]
13. Brozanski BS, Jones JG, Gilmour CH, Effect of pulse dexamethasone therapy on the incidence and severity of chronic lung disease in the very low birth weight infant. J Pediatr 1995; 126:769-776 [CrossRef][Medline]
14. Mammel MC, Green TP, Johnson DE, Thompson TR Controlled trial of dexamethasone therapy in infants with bronchopulmonary dysplasia. Lancet 1983; 1:1356-1358 [CrossRef][Medline]
15. Mammel MC, Fiterman C, Coleman M, Boros SJ Short-term dexamethasone therapy for bronchopulmonary dysplasia: acute effects and 1-year follow-up. Dev Pharm Ther 1987; 10:1-11 [Medline]
16. Kothadia JM, O'Shea TM, Roberts D, Auringer ST, Weaver RG, Dillard I 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. Pediatrics 1999; 104:22-27 [Abstract/Free Full Text]
17. Bourchier D Dexamethasone therapy in severe bronchopulmonary dysplasia. Aust Paediatr J 1988; 24:41-44 [Medline]
18. Rastogi A, Akintorin SM, Bez ML, Morales P, Pildes RS A controlled trial of dexamethasone to prevent bronchopulmonary dysplasia in surfactant-treated infants. Pediatrics 1996; 98:204-210 [Abstract/Free Full Text]
19. Yeh TF, Torre JA, Rastogi A, Anyebuno MA, Pildes RS Early postnatal dexamethasone therapy in premature infants with severe respiratory distress syndrome: a double-blind, controlled study. J Pediatr 1990; 117:273-282 [CrossRef][Medline]
20. Yeh TF Is chronic lung disease (CLD) in premature infants preventable? Acta Paediatr Sinica 1996; 37:241-243
21. Cole CH, Colton T, Shah BL, Early inhaled glucocorticoid therapy to prevent bronchopulmonary dysplasia. N Engl J Med 1999; 340:1005-1010 [Abstract/Free Full Text]
22. Garland JS, Alex CP, Pauly TH, A three-day course of dexamethasone therapy to prevent chronic lung disease in ventilated neonates: a randomized trial. Pediatrics 1999; 104:91-99 [Abstract/Free Full Text]
23. Kovacs L, Davis GM, Faucher D, Papageorgiou A Efficacy of sequential early systemic and inhaled corticosteroid therapy in the prevention of chronic lung disease of prematurity. Acta Paediatr 1998; 87:792-798 [CrossRef][Medline]
24. Co E, Chari G, McCulloch K, Vidyasagar D Dexamethasone treatment suppresses collagen synthesis in infants with bronchopulmonary dysplasia. Pediatr Pulmonol 1993; 16:36-40 [Medline]
25. Greenough A, Emery EF, Gamsu HR Dexamethasone and hypertension in preterm infants. Eur J Pediatr . 1992; 151:134-135
26. Ng PC, Brownlee KG, Dear PR Gastroduodenal perforation in preterm babies treated with dexamethasone for bronchopulmonary dysplasia. Arch Dis Child 1991; 66:1164-1166 [Abstract]
27. O'Neil EA, Chwals WJ, O'Shea MD, Turner CS Dexamethasone treatment during ventilator dependency: possible life threatening gastrointestinal complications. Arch Dis Child 1992; 67:10-11 [Abstract]
28. Van Goudoever JB, Wattimena JD, Carnielli VP, Sulkers EJ, Degenhart HJ, Sauer PJ Effect of dexamethasone on protein metabolism in infants with bronchopulmonary dysplasia. J Pediatr 1994; 124:112-118 [CrossRef][Medline]
29. Werner JC, Sicard RE, Hansen TW, Solomon E, Cowett RM, Oh W Hypertrophic cardiomyopathy associated with dexamethasone therapy for bronchopulmonary. J Pediatr 1992; 120:286-291 [CrossRef][Medline]
30. Kendig JW, Ryan RM, Sinkin RA, Comparison of two strategies for surfactant prophylaxis in very premature infants: a multicenter randomized trial. Pediatrics 1998; 101:1006-1012 [Abstract/Free Full Text]
31. Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988; 82:527-532 [Abstract/Free Full Text]
32. Noble-Jamieson CM, Regev R, Silverman M Dexamethasone in neonatal chronic lung disease: pulmonary effects and intracranial complications. Eur J Pediatr 1989; 148:365-367 [CrossRef][Medline]
33. Collaborative Dexamethasone Trial Group Dexamethasone therapy in neonatal chronic lung disease: an international placebo-controlled trial. Pediatrics 1991; 88:421-427 [Medline]
34. Avery ME, Merritt TA Surfactant-replacement therapy. N Engl J Med 1991; 324:910-912 [Medline]
35. Harkavy KL, Scanlon JW, Chowdhry PK, Grylack LJ Dexamethasone therapy for chronic lung disease in ventilator- and oxygen-dependent infants: a controlled trial. J Pediatr 1989; 115:979-983 [CrossRef][Medline]
36. Kazzi NJ, Brans YW, Poland RL Dexamethasone effects on the hospital course of infants with bronchopulmonary dysplasia who are dependent on artificial ventilation. Pediatrics 1990; 86:722-727 [Abstract/Free Full Text]
37. Papile LA, Tyson JE, Stoll BJ, A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants. N Engl J Med 1998; 338:1112-1118 [Abstract/Free Full Text]
38. Durand M, Sardesai S, McEvoy C Effects of early dexamethasone therapy on pulmonary mechanics and chronic lung disease in very low birth weight infants: a randomized, controlled trial. Pediatrics 1995; 95:584-590 [Abstract/Free Full Text]
39. Kari MA, Heinonen K, Ikonen RS, Koivisto M, Raivio KO Dexamethasone treatment in preterm infants at risk for bronchopulmonary dysplasia. Arch Dis Child 1993; 68:566-569 [Abstract]
40. Tapia JL, Ramirez R, Cifuentes J, The effect of early dexamethasone administration on bronchopulmonary dysplasia in preterm infants with respiratory distress syndrome. J Pediatr 1998; 132:48-52 [CrossRef][Medline]
41. Morris HG Mechanisms of glucocorticoid action in pulmonary disease. Chest 1985; 88:133S-141S [Abstract/Free Full Text]
42. Shinwell ES, Karplus M, Zmora E, Failure of early postnatal dexamethasone to prevent chronic lung disease in infants with respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed 1996; 74:F33-37 [Abstract/Free Full Text]
43. Wang JY, Yeh TF, Lin YJ, Chen WY, Lin CH Early postnatal dexamethasone therapy may lessen lung inflammation in premature infants with respiratory distress syndrome on mechanical ventilation. Pediatr Pulmonol 1997; 23:193-197 [CrossRef][Medline]
44. Watts CL, Bruce MC Effect of dexamethasone therapy on fibronectin and albumin levels in lung secretions of infants with bronchopulmonary dysplasia. J Pediatr 1992; 121:597-607 [CrossRef][Medline]
45. Yeh TF, Lin YJ, Hsieh WS, et al. Early postnatal dexamethasone therapy for the prevention of chronic lung disease in preterm infants with respiratory distress syndrome: a multicenter clinical trial. Pediatrics. 1997;100(4). URL: http://www.pediatrics.org/cgi/content/full/100/4/e3
46. Gerdes JS, Harris MC, Polin RA Effects of dexamethasone and indomethacin on elastase,  1-proteinase inhibitor, and fibronectin in bronchoalveolar lavage fluid from neonates. J Pediatr 1988; 113:727-731 [CrossRef][Medline]
47. Rindfleisch MS, Hasday JD, Taciak V, Broderick K, Viscardi RM Potential role of interleukin-1 in the development of bronchopulmonary dysplasia. J Interferon Cytokine Res 1996; 16:365-373 [Medline]
48. Yoder MC Jr, ., Chua R, Tepper R Effect of dexamethasone on pulmonary inflammation and pulmonary function of ventilator-dependent infants with bronchopulmonary dysplasia. Am Rev Respir Dis 1991; 143:1044-1048 [Medline]
49. Watterberg KL, Scott SM Evidence of early adrenal insufficiency in babies who develop bronchopulmonary dysplasia. Pediatrics 1995; 95:120-125 [Abstract/Free Full Text]
50. Cole CH, Frantz ID III. Role of postnatal steroids for neonatal chronic lung disease. In: Hansen TN, McIntosh N, eds. Current Topics in Neonatology, II. London, UK: WB Saunders Co; 1997:256-280
51. Knoppert DC, Mackanjee HR Current strategies in the management of bronchopulmonary dysplasia: the role of corticosteroids. Neonatal Network 1994; 13:53-60 [Medline]
52. Bhuta T, Ohlsson A Systematic review and meta-analysis of early postnatal dexamethasone for prevention of chronic lung disease. Arch Dis Child Fetal Neonatal Ed 1998; 79:F26-33 [Abstract/Free Full Text]
53. Halliday HL, Ehrenkranz RA. Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database of Systematic Reviews. 1999;2
54. Yeh TF, Lin YJ, Huang CC, et al. Early dexamethasone therapy in preterm infants: a follow-up study. Pediatrics. 1998;101(5). URL: http://www.pediatrics.org/cgi/content/full/101/5/e7
55. Gilmour CH, Sentipal-Walerius JM, Jones JG, Pulse dexamethasone does not impair growth and body composition of very low birth weight infants. J Am Coll Nutr 1995; 14:455-462 [Abstract]
56. O'Shea TM, Kothadia JM, Klinepeter KL, 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]