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The effect of early dexamethasone administration on bronchopulmonary dysplasia in preterm infants with respiratory distress syndrome

The effect of early dexamethasone administration on bronchopulmonary dysplasia in preterm infants with respiratory distress syndrome
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  48 corticoids could prevent or diminish theinflammatory changes that precedechronic pulmonary injury. 18 On the basis of these observations, thefollowing trial was designed to evaluate whether early use of dexamethasone re-duces the incidence of BPD and/or deathin preterm newborns with RDS, treated with mechanical ventilation and exog-enous surfactant. M ETHODS This trial was designed as a multicenter,double-blind, placebo-controlled study.The trial was approved by the local ethicscommittee at each center, and informed parental consent was obtained before ran-domization. Preterm infants from fourneonatology units (all near sea level) wereenrolled between December 1, 1992, andJune 30, 1995, if they met the followinginclusion criteria: birth weight between700 and 1600 gm, clinical and radiologicdiagnosis of RDS, receiving mechanical ventilatory support, and younger than 36hours of age. Exclusion criteria were the presence of a life-threatening congenitalmalformation or chromosomal abnormali-  Administration of exogenous surfactant re-duces barotrauma and death associated with respiratory distress syndrome. 1-5 However, surfactant administration has notreduced the incidence of bronchopul-monary dysplasia that is present in 30% to 40% of infants who weigh less than 1500 gmat birth and require mechanical ventila- tion. 3-8 Different therapeutic strategies have been proposed to prevent or reduce theseverity of BPD. 9 Glucocorticoids, because T  T he effect of early dexamethasone administration on bronchopulmonary dysplasia in preterm infants withrespiratory distress syndrome  José L. Tapia,  MD  , Rodrigo Ramírez,  MD  , Javier Cifuentes,  MD  , Jorge Fabres,  MD  , M. Eugenia Hübner,  MD  , Aldo Bancalari,  MD  , M. Eugenia Mercado,  MD  , Jane Standen,  MD  , and Marisol Escobar,  MD of their antiinflammatory action, have beenused in several clinical trials in the treatmentof infants with established BPD, reducing the use of mechanical ventilation and im- proving pulmonary function. 10-14 Early (first week of life) cytopathologicand cytochemical inflammatory alter-ations are observed in tracheal aspiratesof infants receiving ventilatory support who later experience BPD. 15-17 This led to the hypothesis that early use of gluco-  From the Departamento de Pediatría, Unidad de Neonatología, Hospital Clínico Universidad Católica, Santiago, Chile;Unidad de Neonatología Hospital Clínico Universidad de Chile, Santiago, Chile; Unidad de Neonatología, Hospital Dr.Guillermo Grant, Concepción, Chile; Unidad de Neonatología, Hospital Dr. Gustavo Fricke, Viña del Mar, Chile. Supported by The Wellcome Foundation and Laboratorios Saval.Submitted for publication Nov. 14, 1996; accepted Sept. 16, 1997.Reprint requests: Jose L. Tapia, MD, Departamento de Pediatría, Universidad Católica de Chile, Casilla 114-D, Santiago, Chile.Copyright © 1998 by Mosby, Inc.0022-3476/98/$5.00 + 0  9/21/86238 See related article,p.53. Objectives: This study was carried to evaluate the effect of early administration of dexamethasone on the incidence of bronchopulmonary dysplasia (BPD) and/or deathin surfactant-treated preterm infants with respiratory distress syndrome (RDS). Study design: In a multicenter, double-blind, placebo-controlled trial, 109 preterm in-fants with RDS and birth weights between 700 and 1600 gm, who were treated withmechanical ventilation and surfactant, were randomly assigned before 36 hours of life to receive dexamethasone (  n = 55) or placebo (  n = 54) for 12 days. Results: There were no differences in the incidence of BPD and/or death betweengroups. However, fewer patients in the dexamethasone group were oxygen-dependentat 36 weeks after conception (8% vs 33%,  p < 0.05). The dexamethasone group had a lower incidence of necrotizing enterocolitis (0% vs 9%,  p < 0.05). The incidence of arte-rial hypertension, hyperglycemia, and sepsis was not affected by the treatment. Basaland poststimulation serum cortisol levels did not differ between groups. Conclusion: The administration of dexamethasone early in the course of RDS doesnot decrease the incidence of BPD and/or death in preterm infants. However, dexa-methasone may reduce oxygen dependency at 36 weeks after conception. (J Pediatr1998;132:48-52) BPDBronchopulmonary dysplasiaNECNecrotizing enterocolitisRDSRespiratory distress syndrome  T HE  J OURNALOF P EDIATRICS T APIAETAL .Volume 132,Number 1  ty, a strong suspicion of infection at birth(maternal chorioamnionitis), or early sep-sis (positive cultures of blood obtained in the first 36 hours of life).The preterm infants were randomly as-signed, at each center, to receive dexa-methasone sodium phosphate (Oradexon,Organon Laboratories) or placebo (0.9%saline solution). All the material for ran-domization and the ampoules of both so- lutions were prepared in the hospital pharmacy of one of the centers and were visually indistinguishable. Dexametha-sone was administered intravenouslyevery 12 hours for 12 days by using thefollowing schedule: days 1 to 3, 0.5mg/kg/day; days 4 to 6, 0.25 mg/kg/day;days 7 to 9, 0.12 mg/kg/day; and days 10 to 12, 0.06 mg/kg/day. The placebo groupreceived an equivalent volume of salinesolution. Additional glucocorticoid thera- pies for BPD were not allowed for pa- tients in either treatment group. All patients entered in the study re-ceived synthetic surfactant (Exosurf,Burroughs Wellcome), 5 ml/kg every 12hours, for a total of two doses as an early therapy (as soon as diagnosis of RDS wasconfirmed), administered according tostandard recommendations. 19 Blood cultures were performed for all patients on admission. Cranial ultra-sonography was performed during thefirst 72 hours of life and at 28 days. Chest x-ray studies were performed on admis-sion, as clinically indicated, and at 28days of age. Serum electrolytes, bloodsugar, and arterial blood pressure weremonitored every day during the treat-ment period. Serum cortisol levels weredetermined before (8:00  AM  ) and 1 hourafter administration of 36 µ g/kg of adrenocorticotropic hormone IV (Sinacten), between 48 and 72 hoursafter completion of treatment with eitherdexamethasone or placebo. Other tests were performed on the basis of clinical in-dications. An operative manual was writ- ten for this trial in order to obtain similarapproaches to clinical problems.The primary outcome measure wasBPD at 28 days of life, as defined byBancalari et al., 20 or death before dis-charge, or both. Secondary outcomemeasures were: (1) oxygen dependencyat 36 weeks after conception, (2) numberof days receiving mechanical ventilationand oxygen supplementation, (3) deathand arterial/alveolar oxygen tension ratioat 72 hours of age and weight gain at 28 days of life, (4) incidence of pulmo-nary air leaks, patent ductus arteriosus, pulmonary hemorrhage, intraventricularhemorrhage, necrotizing enterocolitis, in-fection, retinopathy of prematurity, arter-ial hypertension, hyperglycemia, and gas- trointestinal hemorrhage.Pulmonary hemorrhage was defined as the presence of bright red, bloody endo- tracheal tube aspirate, associated with arespiratory deterioration that required in-creasing of oxygen and ventilatory set- tings. Patent ductus arteriosus was diag-nosed clinically and confirmed byechocardiography. The diagnosis of intra- ventricular hemorrhage was made by cra-nial ultrasonography or by autopsy and was classified according to the method of Papile et al. 21 The clinical diagnosis of sepsis was confirmed by the isolation of  the organism in blood or cerebrospinalfluid cultures or by autopsy findings. Thediagnosis of pneumonia was based onclinical and radiologic signs and a positive blood culture. NEC was confirmed by ra-diologic and/or surgical findings. Arterialhypertension was diagnosed when thesystolic pressure was 100 mm Hg orgreater or when the diastolic pressure was70 mm Hg or greater. Hyperglycemia wasdefined as a plasma glucose level of 150mg/dl or greater. According to previous data from the participating units, the expected incidenceof BPD and/or death was 68%. A mini-mum sample size of 108 infants (54 pergroup) was required to observe a de-crease of BPD and/or death from 68% to less than 40%, with a type 1 error of 0.05and a type 2 error of 20% (power of 80%).Categorical variables were compared byeither chi square or Fischer’s exact test.Continuous variables with marked skew-ness of distribution were compared by the Wilcoxon–Mann-Whitney test. Multi- variate analysis was performed with theuse of logistic regression to determine fac- tors affecting primary outcome measures. 49 Placebo group Dexamethasone p Value( n = 54)group ( n = 55) BW (gm, mean ±SD)1074 ±2301176 ±2440.03GA (wk, mean ±SD)28.7 ±1.829.1 ±2NSMales [no. (%)]21 (39)34 (62)0.02Multiple gestation [no. (%)]16 (30)12 (22)NS Antenatal steroid [no. (%)]23 (43)18(33)NSPROM [no. (%)]3 (6)1 (2)NSDelivery [no. (%)] Vaginal11 (20)11 (20)NSPrelabor cesarean section23 (43)25 (45)NSIn labor cesarean section20 (37)19 (35)NSLow Apgar score* [no. (%)]24 (44)23 (42)NSPIH [no. (%)]17 (32)19 (35)NS  BW, Birth weight; GA , gestational age;  NS , not significant;  PROM  , prolonged rupture of membranes;  PIH  , pregnancy-induced hypertension.*Low Apgar score: <4 at 1 minute or <7 at 5 minutes. Table I. Population characteristics  T APIAETAL .T HE  J OURNALOF P EDIATRICS  J ANUARY 1998 cidence of oxygen dependency at 36 weeks after conception (  p < 0.05).The causes of death were comparable in the two groups: seven deaths were caused by intraventricular hemorrhage and five were caused by pulmonary hemorrhage ineach group. The other causes of death in the placebo group were septicemia (  n =3), severe RDS (  n = 2), and NEC (  n = 1).In the dexamethasone group, other caus-es were severe RDS (  n = 4) and severe perinatal asphyxia (  n = 1). At 72 hours of life, the mortality rates were 15% in the placebo group and 24%in the dexamethasone group (  p = NS),and the arterial/alveolar oxygen tensionratio was 0.39 ±0.19 in both groups (  p =NS). Weight gain at 28 days of life was150 ±146 gm in the placebo group versus113 ±137 gm in the dexamethasonegroup (  p = NS).There were no differences in the numberof days of mechanical ventilation and oxy-gen requirement among groups (Table III).There were no differences in the incidenceof major morbidity and possible complica- tions related to steroid administrationamong groups, except for a lower incidenceof NEC in the dexamethasone group(Table IV). There were no cases of gas- trointestinal hemorrhage in either group.Plasma cortisol measurements, deter-mined before and after administration of adrenocorticotropic hormone between 48and 72 hours after discontinuing treat-ment, were not different between groupsin 67 survivors studied (Table V). D ISCUSSION This study shows that dexamethasonegiven to preterm infants with RDS, weighing 700 to 1600 gm, and started be-fore 36 hours of life, did not reduce the in-cidence of BPD and/or death. Nonethe- less, steroid administration was associated with a decrease in the number of infantsrequiring supplemental oxygen at 36 weeks after conception.Several limitations of this study requirefurther discussion. The dexamethasonegroup had higher birth weights and agreater proportion of male infants than the placebo group. Both variables may in-fluence the outcome measures of thestudy. 22-24 However, after controlling for birth weight and gender in the logistic re- 50 R ESULTS  We enrolled 113 infants in the study; twofrom the dexamethasone group were ex-cluded, one because of congenital cysticadenomatoid malformation discovered atautopsy and the other on the fifth day of life because of confirmed early sepsis (withoutBPD). Two patients from the placebogroup were excluded: one had early sepsisconfirmed at autopsy; the other was trans-ferred to another hospital at 2 weeks of age(still receiving oxygen), and no further in-formation could be obtained. Analysis is based on the outcome of the remaining 109infants, 54 in the placebo group and 55 in the group treated with dexamethasone.There were more male infants in the dex-amethasone group (62% vs 39%,  p < 0.05),and their birth weights were higher (1176 ±244 gm vs 1074 ±230 gm,  p < 0.05). Other population characteristics were similar be- tween groups (Table I).There were no significant differences indeath rate and/or BPD between thegroups (Table II). There was a significantreduction in the number of infants re-quiring oxygen at 36 weeks after concep- tion in the dexamethasone group (8% vs33%,  p < 0.05). The stepwise logistic re-gression analysis with oxygen dependen-cy at 36 weeks after conception as the de- pendent variable and birth weight,gestational age, gender, prenatal use of steroids, and study treatment as the inde- pendent variables showed that study treatment was the only variable signifi-cantly associated with the dependent variable. Dexamethasone administration was associated with a reduction in the in- OutcomePlacebo group Dexamethasone ( n = 54)group ( n = 55)No.(%)No.(%)  p ValueRR (95% CI) Death*18 (33)17 (31)0.790.93 (0.54-1.60)BPD†16 (44)11 (29)0.250.65 (0.35-1.20)BPD or death34 (63)28 (51)0.200.81 (0.58-1.12)O 2 at 36 wk‡12 (33)3 (8)0.020.24 (0.07-0.77)  RR , Relative risk; CI  , confidence interval.*Death before discharge (incidence over total group infants).†BPD defined as O 2 at 28 days and x-ray changes (incidence over survivors).‡Incidence over survivors. Table II. Primary outcome and oxygen dependency at 36 weeks after conception Placebo group Dexamethasone p Value( n = 54)group ( n = 55) Days ventilator required11 ±126 ±70.09Days with O 2 >0.40 required4 ±73 ±30.89Days with O 2 required23 ±2517 ±200.32  Values are expressed as means ±SD. Table III. Ventilatory and oxygen requirements  T HE  J OURNALOF P EDIATRICS T APIAETAL .Volume 132,Number 1  tracheal lavage have been found as earlyas the first 24 hours of life in preterm in-fants with endotracheal tubes who laterexperienced BPD. 27 Low plasma cortisol values have been documented during thefirst days of life in very low birth weightinfants who subsequently experiencedBPD. 28,29 This has led to speculation thatselected infants with very low birth weight may benefit from early postnatalsteroid therapy.Comparisons of controlled trials thathave reported on postnatal dexamethasonegiven in the first hours of life to prematureinfants with RDS are difficult to make be-cause there are substantial differences instudy design. Yeh et al., 18 in a 12-day trial with 57 infants weighing 700 to 1999 gm, 51 gression model, dexamethasone adminis- tration did not affect the primary outcomemeasures of BPD and/or death but re-mained the only factor significantly asso-ciated with lower oxygen dependency at36 weeks after conception. There was alsoa high mortality rate in our population,and this can minimize the impact of ther-apies that require patient survival for out-come analysis (e.g., the effect in BPD).The rationale for early postnatal steroidadministration in premature infants withRDS is further supported by recently published data. The peak of bronchoalve-olar inflammatory activity that may lead to BPD occurs during the middle to late part of the first week of life. 25,26 Increasedneutrophil count and elastase activity inreported fewer days on which mechanical ventilation and supplemental oxygen wererequired in those given dexamethasone.This study was done before surfactant therapy was available, and it is known thatsurfactant affects short- and long-term out-comes in RDS. Sanders et al. 30 used only two doses of dexamethasone in 40 infants younger than 30 weeks’ gestation and alsofound fewer days on which mechanical ventilation and oxygen were required in the dexamethasone group. Steroid therapycould have been insufficient, and theirnumber of patients could have been toosmall to demonstrate other differences inoutcome. Shinwell et al., 31 in 248 infants weighing 500 to 2000 gm, did not find anymajor benefit after a 3-day course of dex-amethasone. Furthermore, additionalsteroids were given to almost 30% of theinfants after 1 week of age. This could haveminimized the effects of the initial therapy, the duration of which also might have been too short. Rastogi et al., 32 in a 12-day trialin 70 infants with severe RDS weighing700 to 1500 gm, found a reduction in BPD,oxygen dependency at 36 weeks after con-ception, and number of days on which oxy-gen and mechanical ventilation were re-quired in the dexamethasone group. Thisstudy is very similar to ours, except that in their study a population at higher risk forBPD was selected and their mortality rate was only 8.5%. Also, the study by Rastogiet al. 32 allowed for a reduction of addition-al steroid courses for BPD in the dexa-methasone group. We did not find differences in the inci-dence of major morbidity associated with prematurity, except for a reduction inNEC in the dexamethasone group. Thisfinding is in agreement with a previousstudy 33 and may be due to the effects of steroids on inflammatory mediators, which have been implicated in the patho-genesis of NEC. 34  We did not find an increased incidenceof systemic hypertension, hyperglycemia,or delay in somatic growth, which have been reported to be associated with earlysteroid therapy. 18,31 However, our defini- tion of hypertension was in the highrange, and we only studied weight gain at28 days of life.The normal adrenal function test resultsfound in our infants may be due to our use Placebo group Dexamethasone( n = 54)group ( n = 55)No.(%)No.(%)  p Value Pneumothorax4 (7)4 (7)NSPIE8 (15)5 (9)NSPDA18 (33)13 (24)NSPH7 (13)10 (18)NSPneumonia10 (19)6 (11)NSSepsis15 (28)14 (25)NSNEC5 (9)0 (0)0.03ROP8 (15)7 (13)NSNot evaluated4 (7)5 (9)NS Arterial hypertension2 (4)3 (5)NSHyperglycemia7 (13)9 (16)NSIVH12 (22)15 (27)NSGrades I-II4 (7)9 (16)NSGrades III-IV8 (15)6 (11)NSNot evaluated5 (9)7 (13)NS  PIE  , Pulmonary interstitial emphysema;  PDA , patent ductus arteriosus;  PH  , pulmonary hemorrhage;  ROP  , retinopathy of prematurity;  IVH, intraventricular hemorrhage. Table IV. Major morbidity and complications Placebo groupDexamethasone p Value( n = 34)group ( n = 33) Basal8.6 ±6.07.2 ±4.60.56 After ACTH 28.8 ±8.627.8 ±9.20.47administration ∆ 20.2 ±6.620.0 ±6.70.96  ACTH, Adrenocorticotropic hormone. Values are expressed as means ±SD in micrograms per deciliter ( µ g/dl). ∆ = Post ACTH minus basal plasma cortisol levels. Table V. Plasma cortisol levels  T APIAETAL .T HE  J OURNALOF P EDIATRICS  J ANUARY 1998 52 of lower steroid doses and gradual taper-ing in comparison with some studies thathad documented low plasma cortisol lev-els in infants with BPD who had receiveddexamethasone. 35,36 Trials with an appropriate sample sizecalculated to determine risks versus bene-fits of early steroid therapy and consider-ing dosage, duration of treatment, andstarting age seem to be justified. A patientselection criteria that only includes infantsat high risk for BPD should reduce thenumber of patients unnecessarily exposed to these treatments. We thank Dr. Waldemar Carlo and Dr. IleneSosenko for their help in preparing this manuscript  and Mr. Luis Villarroel for his statistical assis-tance. We are grateful to the nurse coordinators of this trial, Mrs. Angelica Marguirot and Mrs. Elena Alvarez. R EFERENCES 1.Halliday HL. Surfactant replacement ther-apy. Pediatr Pulmonol 1995;S1:96-7.2.Hennes HM, Lee MB, Rimm AA, ShapiroDL. Surfactant replacement therapy in res- piratory distress syndrome. Meta-analysisof clinical trials of single-dose surfactant ex- tracts. Am J Dis Child 1991;145:102-4.3.Schwartz RM, Luby AM, Scanlon JW,Kellogg RJ. Effect of surfactant on morbid-ity, mortality and resource use in newborninfants weighing 500 to 1500 g. N Engl JMed 1994;330:1476-80. 4.Soll RF, Merritt TA, Hallman M.Surfactant in the prevention and treatmentof respiratory distress syndrome. In:Boynton BR, Carlo WA, Jobe AM, editors.New therapies for neonatal respiratory fail-ure. 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