Early Postnatal Dexamethasone Therapy for the Prevention of Chronic Lung Disease in Preterm Infants With Respiratory Distress Syndrome: A Multicenter Clinical Trial

Objectives. To study whether early postnatal (<12 hours) dexamethasone therapy reduces the incidence of chronic lung disease in preterm infants with respiratory distress syndrome. Materials and Methods. A multicenter randomized, double-blind clinical trial was undertaken on 262 (saline placebo, 130; dexamethasone, 132) preterm infants (<2000 g) who had respiratory distress syndrome and required mechanical ventilation shortly after birth. The sample size was calculated based on the 50% reduction in the incidence of chronic lung disease when early dexamethasone is used, allowing a 5% chance of a type I error and a 10% chance of a type II error. For infants who received dexamethasone, the dosing schedules were: 0.25 mg/kg/dose every 12 hours intravenously on days 1 through 7; 0.12 mg/kg/dose every 12 hours intravenously on days 8 through 14; 0.05 mg/kg/dose every 12 hours intravenously on days 15 through 21; and 0.02 mg/kg/ dose every 12 hours intravenously on days 22 through 28. A standard protocol for respiratory care was followed by the participating hospitals. The protocol emphasized the criteria of initiation and weaning from mechanical ventilation. The diagnosis of chronic lung disease based on oxygen dependence and abnormal chest roentgenogram was made at 28 days of age. To assess the effect of dexamethasone on pulmonary inflammatory response, serial tracheal aspirates were assayed for cell counts, protein, leukotriene B4, and 6-keto prostaglandin F1a. All infants were observed for possible side effects, including hypertension, hyperglycemia, sepsis, intraventricular hemorrhage, retinopathy of prematurity, cardiomyopathy, and alterations in calcium homeostasis, protein metabolism, and somatic growth. Results. Infants in the dexamethasone group had a significantly lower incidence of chronic lung disease than infants in the placebo group either judged at 28 postnatal days (21/132 vs 40/130) or at 36 postconceptional weeks (20/132 vs 37/130). More infants in the dexamethasone group than in the placebo group were extubated during the study. There was no difference between the groups in mortality (39/130 vs 44/132); however, a higher proportion of infants in the dexamethasone group died in the late study period, probably attributable to infection or sepsis. There was no difference between the groups in duration of oxygen therapy and hospitalization. Early postnatal use of dexamethasone was associated with a significant decrease in tracheal aspirate cell counts, protein, leukotriene B4, and 6-keto prostaglandin F1a, suggesting a suppression of pulmonary inflammatory response. Significantly more infants in the dexamethasone group than in the placebo group had either bacteremia or clinical sepsis (43/132 vs 27/130). Other immediate, but transient, side effects observed in the dexamethasone group are: an increase in blood glucose and blood pressure, cardiac hypertrophy, hyperparathyroidism, and a transient delay in the rate of growth. Conclusions. In preterm infants with severe respiratory distress syndrome requiring assisted ventilation shortly after birth, early postnatal dexamethasone therapy reduces the incidence of chronic lung disease, probably on the basis of decreasing the pulmonary inflammatory process during the early neonatal period. Infection or sepsis is the major side effect that may affect the immediate outcome. Other observable side effects are transient. In view of the significant side effects and the lack of overall improvement in outcome and mortality, and the lack of long term follow-up data, the routine use of early dexamethasone therapy is not yet recommended. Pediatrics 1997;100(4). URL: http://www.pediatrics.org/ cgi/content/full/100/4/e3; respiratory distress syndrome, prevention of chronic lung disease, early dexamethasone therapy. ABBREVIATIONS. CLD, chronic lung disease; RDS, respiratory distress syndrome; CPAP, continuous positive airway pressure; Fio2, fraction of inspired oxygen; IVH, intraventricular hemorrhage; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity; BUN, blood urea nitrogen; LTB4, leukotriene B4; 6-ketoPGF1a, 6-keto prostaglandin F1a. Various studies suggest that pulmonary inflammation may play an important role in the early development of chronic lung disease (CLD) in preterm infants on mechanical ventilation.1–5 Because the lung inflammation may occur early in the postnatal life2,6 and the antiinflammatory effect of steroids is usually seen only after 48 to 72 hours of therapy,7 we hypothesize that an early postnatal administration of dexamethasone within 12 hours after birth may prevent the subsequent development of CLD. Based on this hypothesis, we have conducted a multicenter randomized, double-blind clinical trial to answer the following four questions: 1) Does early intravenous dexamethasone therapy, From the *Department of Pediatrics, National Cheng Kung University Hospital, Tainan; ‡Chang Gung Children‘s Hospital and ¶Mackay Memorial Hospital, Taipei; §China Medical College Hospital, iChung Shan Medical College Hospital, and #Kuang Tien Hospital, Taichung, Taiwan, Republic of China. Received for publication Jan 22, 1997; accepted Apr 21, 1997. Reprint requests to (T.F.Y.) Department of Pediatrics, National Cheng Kung University Hospital, 138, Sheng Li Road, Tainan, Taiwan, Republic of China. PEDIATRICS (ISSN 0031 4005). Copyright © 1997 by the American Academy of Pediatrics. http://www.pediatrics.org/cgi/content/full/100/4/e3 PEDIATRICS Vol. 100 No. 4 October 1997 1 of 8 by guest on September 23, 2017 http://pediatrics.aappublications.org/ Downloaded from given within 12 hours after birth for 1 week and then tapering off in 3 weeks, reduce the incidence of CLD? 2) Does early dexamethasone therapy reduce pulmonary inflammatory reaction and improve pulmonary status? 3) Does early dexamethasone therapy improve mortality and overall outcome? 4) What are the side effects of early dexamethasone therapy? MATERIALS AND METHODS During a 30-month period (October 1992 to April 1995), all infants with birth weights of 500 to 1999 g (National Cheng Kung University Hospital, Chang Gung Children’s Hospital, Mackay Memorial Hospital, China Medical College Hospital, Chung Shan Medical College Hospital, and Kuang Tien Hospital in Taiwan) were eligible for the study. The criteria of selection were: 1) severe radiographic respiratory distress syndrome (RDS) requiring mechanical ventilation within 6 hours after birth and 2) the absence of prenatal infection, complex congenital anomalies, and lethal cardiopulmonary status. This study was approved by the scientific and human experimental committees of the participating hospitals. Informed consent was obtained from the parents. Sample Size Calculation and Placebo/Dexamethasone Regimen A previous survey in Taiwan indicated that approximately 40% of infants fulfilling the proposed inclusion criteria would develop CLD at 28 days of age. Using the sample-size tables of Fleiss8 and using the 40% incidence in the placebo group and an expected 50% reduction in the dexamethasone-treated group, 127 infants in each group is required to detect the difference, permitting a 5% chance of a type I error and a 10% chance of a type II error. Allowing for attrition and exclusions from the final study groups, 135 was considered a safe target number for each group. The numbers 1 through 270 were assigned at random either to the placebo or the dexamethasone group. When the first dose of placebo/dexamethasone was prescribed, the pharmacist in the central pharmacy of National Cheng Kung University Hospital would open the assignment list to determine whether dexamethasone or placebo should be dispensed. Four vials of either dexamethasone or saline placebo were prepared, one vial for each week. If placebo was indicated, each vial containing 10 mL of saline only would be prepared and if dexamethasone was indicated, each vial containing 10 mL of a solution of 20 mg, 10 mg, 5 mg, and 2.5 mg dexamethasone, respectively, would be prepared. A total of 56 doses of dexamethasone or saline solution were given intravenously for 4 weeks. This dosage corresponded to the following schedule (one dose every 12 hours) for the intravenously administered solution containing dexamethasone sodium phosphate: days 1 through 7, 0.25 mg/kg/dose; days 8 through 14, 0.12 mg/kg/dose; days 15 through 21, 0.05 mg/kg/dose; and days 22 through 28, 0.02 mg/kg/dose. Diagnosis and Treatment of RDS The diagnosis of RDS was made according to clinical and radiographic features. A protocol for the treatment of infants with RDS was followed by the participating hospitals. Blood gas samples were obtained through an umbilical arterial catheter or from a peripheral artery. The criteria for initiation of continuous positive airway pressure (CPAP) would include either of the following: 1) arterial partial pressure of oxygen ,50 mm Hg with the fraction of inspired oxygen (Fio2) $.4, or 2) apnea. Intermittent mandatory ventilation was initiated if there was: 1) failure to respond to CPAP; 2) arterial partial pressure of oxygen ,50 mm Hg; Fio2 $.6; 3) arterial partial pressure of carbon dioxide .60 mm Hg; or 4) repeated or prolonged apnea. Weaning from mechanical ventilation started as soon as there was an improvement in blood gas values and clinical condition. Once the peak ventilatory pressure was ,25 cm H2O, the inspired oxygen concentration was decreased, with a 5% reduction each time, and the arterial or arterialized oxygen tension was maintained at appropriate levels. When the inspired oxygen concentration had been reduced to 40%, attempts were made to speed up the weaning process by decreasing the ventilatory rate. Once the rate has been reduced to 5 to 10 per minute, continuous distending pressure was instituted, with pressure adequate to maintain appropriate blood gas values. The pressure was then reduced until it reached 2 cm H2O. If the blood gas values remained appropriate, attempts to remove the endotracheal tube were initiated. After endotracheal suction and manual ventilation, the tube was removed during a full inflation of the lungs. The infant was then placed in a hood with an environmental oxygen concentration 10% higher than that before removal of the tube. Total fluid intake was adjust to 80 mL/kg/d in the first postnatal day and increased daily to 150 mL/kg/d by day 5 and onward. Because of the possible risk of infection associated with steroid therapy, all infants were given ampicillin and gentamicin for 7 days. Subsequently the use of antibiotics was judged by the service attending physician. Blood culture was obtained for any infant suspected to have sepsis. Clinical suspicion of sepsis was made if the infant had clinical signs of lethargy and poor sucking and had increases in immature neutrophile or elevation of C-reactive protein.9 After completion of the study at 4-weeks postnatal day, the infants were treated at the discretion of the attending physician and house staff who were not aware of the therapy. Surfactant was not commercially available in Taiwan at the time when this study was started; therefore, none of these infants received surfactant. The diagnosis of CLD was made if the infant had: 1) respiratory distress requiring supplemental oxygen therapy for 28 days or longer, and 2) an abnormal chest radiograph. Evaluation of Possible Side Effects All infants were observed for hypertension, hyperglycemia, sepsis, intraventricular hemorrhage (IVH), patent ductus arteriosus (PDA), retinopathy of prematurity (ROP), and somatic growth. Cardiac echocardiograph and calcium homeostasis were also evaluated in the first 50 infants. The following variables were measured before and on days 1, 3, 5, 7, 10, 14, 21, and 28 after starting the study: urine output, urine electrolytes and osmolality, urine calcium, phosphorous and creatinine, serum electrolytes, creatinine, blood urea nitrogen (BUN), osmolality, calcium, phosphorous, and parathyroid hormone. Body weight, length, head circumference, and bone length and width by radiograph (longest axis and midpoint medullary diameter of femur) were all recorded weekly during the study.