A controlled trial of dexamethasone in preterm infants at high risk for bronchopulmonary dysplasia. Efficacy of sequential early systemic and inhaled corticosteroid therapy in the prevention of chronic lung disease of prematurity. Effect of pulse dexamethasone therapy on the incidence and severity of chronic lung disease in the very low birth weight infant. Low-dose dexamethasone facilitates extubation among chronically ventilator-dependent infants: a multicenter, international, randomized, controlled trial. Effects of early dexamethasone therapy on pulmonary mechanics and chronic lung disease in very low birth weight infants: a randomized, controlled trial. Dexamethasone effects on the hospital course of infants with bronchopulmonary dysplasia who are dependent on artificial ventilation. A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants. Effect of dexamethasone on tracheobronchial aspirate fluid cytology and pulmonary mechanics in preterm infants. Dexamethasone therapy in neonatal chronic lung disease: an international placebo-controlled trial. Collaborative Dexamethasone Trial Group. Controlled trial of dexamethasone in respirator-dependent infants with bronchopulmonary dysplasia. Randomized controlled trial of dexamethasone treatment in very-low-birth-weight infants with ventilator-dependent chronic lung disease. 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. Dexamethasone in neonatal chronic lung disease: pulmonary effects and intracranial complications. Dexamethasone therapy for chronic lung disease in ventilator- and oxygen-dependent infants: a controlled trial. Adrenal suppression and extubation rate after moderately early low-dose dexamethasone therapy in very preterm infants.
We evaluated the use of dexamethasone in preterm infants to decrease morbidity associated with bronchopulmonary dysplasia in a randomized, double-blind, placebo-controlled trial. Thirty-six preterm infants (birth weight, less than or equal to 1250 g and gestational age, less than or equal to 30 weeks) who were dependent on oxygen and mechanical ventilation at two weeks of age received a 42-day course of dexamethasone (n = 13), an 18-day course of dexamethasone (n = 12), or saline placebo (n = 11). The starting dose of dexamethasone was 0.5 mg per kilogram of body weight per day, and it was progressively lowered during the period of administration. Infants in the 42-day dexamethasone group, but not those in the 18-day group, were weaned from mechanical ventilation significantly faster than control infants (medians 29, 73, and 84 days, respectively; P less than 0.05), and from supplemental oxygen (medians 65, 190, and 136 days, respectively; P less than 0.05). No clinical complications of steroid administration were noted. Follow-up of all 23 survivors at 6 and 15 months of age showed good outcome (normal neurologic examinations and Bayley Developmental Indexes greater than or equal to 84) in 7 of the 9 infants in the 42-day dexamethasone group, but in only 2 of the 9 infants in the 18-day dexamethasone group and 2 of the 5 in the placebo group (P less than 0.05). We conclude that dexamethasone therapy for 42 days improves pulmonary and neurodevelopmental outcome in very-low-birth-weight infants at high risk for bronchopulmonary dysplasia. In order to assess the efficacy of a combination of systemic and nebulized corticosteroids in reducing the incidence and severity of chronic lung disease (CLD) in very low birthweight (VLBW) infants, 60 ventilator-dependent infants < or = 1500 g were randomly assigned to receive either steroids or placebo as of 7 d. The steroid group (n = 30, GA = 25.8 +/- 1.6 weeks, BW = 731 +/- 147 g) received systemic dexamethasone for 3 d, followed by nebulized budesonide for 18 d. Control infants (n = 30, GA = 25.9 +/- 1.8 weeks, BW = 796 +/- 199 g) received systemic and inhaled saline. Steroid-treated infants required less ventilatory support between 9 and 17 d (p < 0.01), and had greater lung compliance at 10 d (p = 0.01), but not subsequently. CLD incidence at 36 weeks was 45.5% vs 56.0% in controls, and fewer steroid-treated infants required dexamethasone rescue (23.3% vs 56.7%, p = 0.017). Survival to discharge was similar (73.3% vs 83.3%), as were the durations of mechanical ventilation, supplemental oxygen use, and hospitalization. Tracheal effluent elastase/albumin ratios and serum cortisol values did not differ between groups, and no adverse effects were noted. We conclude that early dexamethasone administration was associated with improved pulmonary function, which was not sustained with nebulized budesonide. However, the steroid regimen studied reduced the need for dexamethasone rescue in infants with CLD. We conducted a prospective, randomized, double-blind trial to assess the efficacy and safety of pulse doses of dexamethasone on survival without supplemental oxygen in very low birth weight infants at high risk of having chronic lung disease. Seventy-eight infants with birth weights < or = 1500 gm who were ventilator dependent at 7 days of postnatal age were randomly assigned to receive pulse doses of dexamethasone, 0.5 mg/kg per day, divided twice daily (n = 39), or an equivalent volume of saline solution placebo (n = 39), for 3 days at 10-day intervals until they no longer required supplemental oxygen or assisted ventilation, or reached 36 weeks of postmenstrual age. At study entry, the groups did not differ by birth weight, gestational age, or severity of lung disease. At 36 weeks of postmenstrual age, there was both a significant increase in survival rates without oxygen supplementation (p = 0.03) and a significant decrease in the incidence of chronic lung disease (p = 0.047) in the group that received pulse therapy. Supplemental oxygen requirements were less throughout the study period in the group that received repeated pulse doses of dexamethasone (p = 0.013). The total numbers of deaths and the durations of supplemental oxygen, ventilator support, and hospital stay did not differ between groups. Recorded side effects in the pulse therapy group were minimal and included an increase in the use of insulin therapy for hyperglycemia (p < 0.05). We conclude that in this population of very low birth weight infants, treatment with pulse doses of dexamethasone resulted in improvement in pulmonary outcome without clinically significant side effects. Postnatal corticosteroid therapy is controversial. The aim of this study was to determine the short-term effects of low-dose dexamethasone treatment among chronically ventilator-dependent neonates.
                Very preterm (gestational age: <28 weeks) or extremely low birth weight (birth weight: <1000 g) infants who were ventilator dependent after the first 1 week of life were eligible and were assigned randomly to receive masked dexamethasone (0.89 mg/kg over 10 days) or saline placebo. Data on ventilator and oxygen requirements and deaths were recorded.
                Seventy infants were recruited from 11 centers, at a median age of 23 days. More infants were extubated successfully by 10 days of treatment in the dexamethasone group (60%, 21 of 35 patients) than in the control group (12%, 4 of 34 patients) (odds ratio [OR]: 11.2; 95% confidence interval [CI]: 3.2-39.0). Ventilator and oxygen requirements improved substantially, and the duration of intubation was shorter. There was little evidence for a reduction in either the mortality rate (dexamethasone group: 11%; control group: 20%; OR: 0.52; 95% CI: 0.14-1.95) or the rate of oxygen dependence at 36 weeks (dexamethasone group: 85%; control group: 91%; OR: 0.58; 95% CI: 0.13-2.66). There were no obvious effects of low-dose dexamethasone on blood glucose concentrations, blood pressure, or other complications. No infant experienced intestinal perforation.
                Low-dose dexamethasone treatment after the first 1 week of life clearly facilitates extubation and shortens the duration of intubation among ventilator-dependent, very preterm/extremely low birth weight infants, without any obvious short-term complications. Combined with recent evidence that infants at very high risk of bronchopulmonary dysplasia may benefit in the long term, our study reopens debate regarding the role of low-dose, late postnatal, corticosteroid therapy. To determine the changes in pulmonary mechanics before and during early dexamethasone therapy, and to evaluate the effect of dexamethasone on the duration of mechanical ventilation in very low birth weight (VLBW) ventilator-dependent infants at risk for chronic lung disease (CLD).
                A prospective randomized trial was conducted. Forty-three patients (birth weight 600 to 1500 g, gestational age 24 to 32 weeks) who failed to be weaned from the respirator at 7 to 14 days of age were enrolled; 23 infants received a 7-day course of dexamethasone (0.5 mg/kg/day intravenously for 3 days, 0.25 mg/kg/day for 3 days, and 0.1 mg/kg/day for 1 day), and 20 patients were in the control group. At similar mean airway pressure (MAP) and fractional inspired oxygen concentration (FiO2), respiratory system mechanics were measured before and on days 2, 5, and 7 of the study. Airway pressure, flow and tidal volume (VT) were recorded and only mechanical breaths were analyzed. Respiratory compliance (Crs) and respiratory resistance (Rrs) were calculated by two factor least mean square analysis.
                Eighty-three percent of infants in the dexamethasone group and 90% in the control group received surfactant in the first 24 hours of life. There was a significant increase in Crs and VT in the dexamethasone group as compared with the control group (P < .001). No major changes in Rrs were observed. Dexamethasone therapy significantly decreased FiO2 and MAP P < .001) and facilitated successful weaning from mechanical ventilation. In addition to a shorter duration of mechanical ventilation (P < .01), the occurrence of CLD (FiO2 > 0.21 at 36 weeks of corrected gestational age, chest radiograph changes) was significantly decreased in the dexamethasone group (P < .01). Except for a transient increase in blood pressure and serum glucose, there were no significant differences in infection rates, intraventricular hemorrhage, or retinopathy of prematurity. Thirteen patients in the control group received dexamethasone at a later age.
                Our findings indicate that: 1) early dexamethasone therapy in VLBW infants markedly improves respiratory compliance and tidal volume, reduces FiO2 and MAP requirements, and facilitates extubation in these infants; 2) early dexamethasone therapy reduces the duration of mechanical ventilation and decreases CLD (at 28 days and 36 weeks) in a population of VLBW infants largely treated with surfactant. A randomized double-blind placebo-controlled trial was conducted to evaluate the effects of enterally administered dexamethasone on the hospital course of infants with bronchopulmonary dysplasia. A total of 23 infants with a birth weight less than 1500 g who were dependent on artificial ventilation 3 to 4 weeks of age received dexamethasone (n = 12) or saline placebo (n = 11). Dexamethasone (0.5 mg/kg per day) was given in tapering doses for 7 days followed by hydrocortisone (8 mg/kg per day) which was progressively reduced for a total of 17 days of therapy. Infants who received dexamethasone required less oxygen on days 8 and 17 (P less than .05) and were more likely to extubate 8 days after therapy than infants in the control group (respectively 8/12 vs 3/11 infants, P less than .05; P = .12 after Yates correction). The use of dexamethasone significantly shortened median duration of mechanical ventilation (4 vs 22 days, P less than .05) but had no effect on length of oxygen therapy, hospitalization, home oxygen therapy, occurrence and severity of retinopathy of prematurity, rate of growth, and mortality. No significant complications resulted from dexamethasone therapy. Measurements of plasma dexamethasone levels confirmed the absorption of drug from the gastrointestinal tract (23.7 ng/mL in dexamethasone vs 4.6 ng/mL in the control group, P less than .05). Dexamethasone administration resulted in short-term improvements in pulmonary function but did not ameliorate the hospital course of infants with bronchopulmonary dysplasia. Ventilator-dependent premature infants are often treated with dexamethasone. However, the optimal timing of therapy is unknown.
                We compared the benefits and hazards of initiating dexamethasone therapy at two weeks of age and at four weeks of age in 371 ventilator-dependent very-low-birth-weight infants (501 to 1500 g) who had respiratory index scores (mean airway pressure x the fraction of inspired oxygen) of 52.4 at two weeks of age. One hundred eighty-two infants received dexamethasone for two weeks followed by placebo for two weeks, and 189 infants received placebo for two weeks followed by either dexamethasone (those with a respiratory-index score of > or =2.4 on treatment day 14) or additional placebo for two weeks. Dexamethasone was given at a dose of 0.25 mg per kilogram of body weight twice daily intravenously or orally for five days, and the dose was then tapered.
                The median time to ventilator independence was 36 days in the dexamethasone-placebo group and 37 days in the placebo-dexamethasone group. The incidences of chronic lung disease (defined as the need for oxygen supplementation at 36 weeks' postconceptional age) were 66 percent and 67 percent, respectively. Dexamethasone was associated with an increased incidence of nosocomial bacteremia (relative risk, 1.5; 95 percent confidence interval, 1.1 to 2.1) and hyperglycemia (relative risk, 1.9; 95 percent confidence interval, 1.2 to 3.0) in the dexamethasone-placebo group, elevated blood pressure (relative risk, 2.9; 95 percent confidence interval, 1.2 to 6.9) in the placebo-dexamethasone group, and diminished weight gain and head growth (P< 0.001) in both groups.
                Treatment of ventilator-dependent premature infants with dexamethasone at two weeks of age is more hazardous and no more beneficial than treatment at four weeks of ages. The changes induced on respiratory mechanics and on tracheobronchial aspirate fluid (TAF) cytology by dexamethasone courses started at two different postnatal ages in preterm infants at risk of chronic lung disease (CLD) were reported in this clinical trial designed in two phases. The first phase of the study included 20 neonates with birth weight < or = 1,250 g and gestational age < or = 32 weeks, who were oxygen and ventilator dependent on the 10th day of life. They were randomly assigned to the moderately early dexamethasone (MED) group or to the control group. The second phase of the study included 20 neonates with the same characteristics, oxygen and ventilator dependent on the 4th day of life, randomly assigned to the early dexamethasone (ED) group or to the control group. Both treated groups received dexamethasone intravenously for 7 days (0.5 mg/kg/day for the first 3 days, 0.25 mg/kg/day for the next 3 days, and 0.125 mg/kg/day for the last day of treatment). The control groups received no steroid treatment. A significantly lower absolute cell count and percentage of neutrophils (PMN) in the TAF and significantly higher dynamic lung compliance (Cdyn) values were observed in both the MED treated compared to the untreated infants and the ED treated infants compared to the control group. Moreover these changes were more precocious in the ED Group compared to the MED Group. Our study suggests that dexamethasone could be more efficacious in reducing effects of ventilator-induced lung injury in preterm infants at high risk of CLD when started earlier.
                Copyright 2004 S. Karger AG, Basel In a multicenter trial of steroid therapy for chronic neonatal oxygen dependence, 287 neonates were randomly allocated from around 3 weeks of age, to dexamethasone or placebo. Active treatment significantly reduced the duration of further assisted ventilation among infants who were ventilator dependent at entry (median days for survivors, 11 vs 17.5). There were no statistically significant differences between the total groups of survivors in time receiving supplemental oxygen and length of stay in hospital, although the trend favored the dexamethasone group. Twenty-five infants in each group died prior to hospital discharge; most were ventilator dependent at trial entry. Open treatment with steroids was later given to 18% in the active group and to 43% in the placebo group. There was no evidence of serious side effects; in particular, infection rates were similar in the two groups. A randomized trial was conducted of dexamethasone therapy in infants with bronchopulmonary dysplasia who were dependent on respirators and were not progressing clinically despite conventional treatment. Babies were admitted to the study if they had a roentgenogram and clinical diagnosis of bronchopulmonary dysplasia, were 2 to 6 weeks in age, weighed less than 1,500 g, had made no progress in weaning for the preceding five days, and were free of sepsis, patent ductus arteriosus, and congenital heart disease, and had had no intravenous fat for at least 24 hours. After parental consent was obtained, infants were randomly assigned to control or treatment groups. The study hypothesis was that with steroid treatment, babies could be weaned from the respirator within 72 hours and would show a significant improvement in lung compliance within that time. Sequential analysis exceeded criterion (P less than .05) when seven consecutive untied pairs showed weaning with dexamethasone and failure to wean in control infants. Pulmonary compliance improved by 64% in the treated group and 5% in the control group (P less than .01). No significant intergroup differences were noted in mortality, length of hospital stay, sepsis, hypertension, hyperglycemia, or electrolyte abnormalities. Study design permits the conclusion that dexamethasone can produce substantial short-term improvement in lung function, often permitting rapid weaning from the respirator, but long-term efficacy and safety must be demonstrated by further investigations. This randomized controlled trial was designed to answer the question: does administration of dexamethasone to neonates with bronchopulmonary dysplasia decrease the need for assisted ventilation? Twenty-five infants with a birth weight < 1501 g, requiring mechanical ventilation and FiO2 of > or = 0.30 at 21-35 days of age, were randomized to treatment with iv dexamethasone or to sham injections for 12 days. The primary outcome criterion was extubation within seven days after study entry. Treatment (n = 12) and control (n = 13) groups were well matched at entry. Dexamethasone facilitated weaning from assisted ventilation (p = 0.0154). There was no increased incidence of infection. Dexamethasone treatment resulted in a significant increase in glucosuria (p = 0.0002) and in systolic blood pressure (p = 0.0034). There was a significant decrease in heart rate (p = 0.0001) and a significant weight loss (p = 0.0002) following dexamethasone treatment. Dexamethasone treatment facilitated weaning from assisted ventilation but several systemic effects were noted that deserve further evaluation before dexamethasone becomes routine treatment. To assess the effect on duration of ventilator dependency of a 42-day tapering course of dexamethasone in very low birth weight neonates.
                Infants (N = 118) were assigned randomly, within birth weight/gender strata, to treatment with either a 42-day tapering course of dexamethasone or an equal volume of saline as placebo. Entry criteria were 1) birth weight <1501 g; 2) age between 15 and 25 days; 3) <10% decrease in ventilator settings for 24 hours and FIO2 >/=0.3; 4) absence of patent ductus arteriosus, sepsis, major congenital malformation, congenital heart disease; and 5) no evidence of maternal HIV or hepatitis B infection. The dosage schedule was 0.25 mg/kg bid for 3 days, then 0.15 mg/kg bid for 3 days, then a 10% reduction in the dose every 3 days until a dose of 0.1 mg/kg had been given for 3 days, from which time a dose of 0.1 mg/kg qod was continued until 42 days after entry. The primary endpoint was the number of days on assisted ventilation after study entry. Secondary outcomes of interest included days on supplemental oxygen, days of hospitalization, and potential adverse effects, such as infection, gastrointestinal bleeding, left ventricular hypertrophy, and severe retinopathy of prematurity.
                Infants in the dexamethasone- and placebo-treated groups were similar in terms of baseline attributes, including birth weight, gestational age, gender, race, and ventilator settings at entry. Infants treated with dexamethasone were on assisted ventilation and supplemental oxygen for fewer days after study entry (median days on ventilator, 5th and 95th percentiles, 13 [1-64] vs 25 [6-104]; days on oxygen, 59 [6-247] vs 100 [11-346]). No differences were found in risk of death, infection, or severe retinopathy. In subgroup analyses, the association of dexamethasone with more rapid weaning from the ventilator was weaker among infants enrolled before the 16th day of life, infants with chest radiographs showing cystic changes and/or hyperinflation, and infants requiring an FIO2 >/=0.7 or a peak inspiratory pressure >/=19 at study entry.
                A 42-day tapering course of dexamethasone decreases the duration of ventilator and oxygen dependency in very low birth weight infants and is not associated with an increased risk of short-term adverse effects. Eighteen infants were entered into a randomized, placebo-controlled trial of dexamethasone therapy for chronic lung disease. Initial ventilation requirements were similar in the two groups, although all infants were in headbox oxygen on entry to the trial. The dexamethasone-treated infants showed a significantly more rapid improvement during the 1st week of treatment, although the overall duration of oxygen therapy was similar in both groups. Cranial ultrasound examination revealed new periventricular abnormalities in three out of the five dexamethasone-treated infants who had previously normal scans, compared with none of four similar placebo-treated infants. A large trial, focussing on potential complications, is now needed. To determine whether dexamethasone therapy altered the outcome of chronic lung disease in neonates, we conducted a prospective, randomized, placebo-controlled trial. Twenty-one 30-day-old oxygen- and ventilator-dependent infants were enrolled. The mean (+/- SD) birth weight was 808.1 +/- 141 gm and the mean gestational age was 26.0 +/- 1.5 weeks. There were 17 black and 12 male infants. Twelve received placebo and nine received dexamethasone. Neither severity of early illness, birth weight, gestational age, age when treated, gender and race distribution, nor frequency of diuretic therapy differed significantly between groups. The age at extubation, 57.2 days (placebo) versus 39.4 days (steroid), was significantly different. The average oxygen requirements of the steroid-treated patients was significantly lower than for placebo-treated patients during the first 10 days of treatment. There were no differences for placebo-versus steroid-treated patients in age when weaned to room air (95.5 days vs 74.9 days), age at discharge (119 days vs 111 days), or number of deaths (2 (17%) vs 1 (11%]. Dexamethasone therapy was associated with a significantly increased incidence of hyperglycemia (89% vs 8%) but did not influence the incidence of hypertension, intracranial hemorrhage, infection, or retinopathy of prematurity. The steroid-treated patients had a significant delay in weight gain during the first 3 weeks of treatment but recovered by discharge. Our results suggest that dexamethasone produces acute improvement in infants with lung disease but no long-term effect on mortality rate, duration of oxygen requirement or age at discharge. A short course of moderately early dexamethasone therapy with a starting dose of 0.5 mg/kg/day improves lung compliance and shortens the duration of ventilatory support in preterm infants with respiratory distress syndrome (RDS). We conducted a double-blind, randomized study to evaluate whether a moderately early 14-day weaning course of low-dose dexamethasone affects adrenal function and facilitates weaning from the ventilator.
                Thirty-six preterm infants with a gestational age < or =32 weeks who required ventilatory support for RDS on days 7-14 were randomized to a 14-day treatment course with dexamethasone (0.2 mg/kg/day start, tapering doses) or placebo (equivalent amounts of normal saline). Prior to the first study treatment and the day after completion of the treatment course, adrenal function was assessed from serum cortisol levels drawn before and 30 min after intravenous administration of 0.1 mg Cortrosyn. Extubation rate during treatment in both groups was compared.
                In both groups baseline serum cortisol levels decreased significantly during treatment, but stimulated cortisol levels did not change. After the 14-day treatment course, stimulated cortisol levels increased significantly from baseline levels in both groups (p<0.001), following Cortrosyn administration. More infants in the dexamethasone group were extubated within 7-14 days of study entry than in the placebo group (p<0.05). Hyperglycemia was more frequently diagnosed in the dexamethasone group and open-label dexamethasone treatment was given more frequently in the control group.
                A moderately early 14-day weaning course of low-dose dexamethasone does not significantly suppress the adrenal function of very preterm infants with RDS, but accelerates weaning from the ventilator.
The benefits of late corticosteroid therapy may not outweigh actual or potential adverse effects. Although there continues to be concern about an increased incidence of adverse neurological outcomes in infants treated with postnatal steroids (see also review of "Early postnatal corticosteroids for preventing chronic lung disease in preterm infants"), this review of postnatal corticosteroid treatment for CLD initiated after seven days of age suggests that late therapy may reduce neonatal mortality without significantly increasing the risk of adverse long-term neurodevelopmental outcomes. However, the methodological quality of the studies determining the long-term outcome is limited in some cases; in some studies the surviving children have only been assessed before school age when some important neurological outcomes cannot be determined with certainty, and no study was sufficiently powered to detect increased rates of important adverse long-term neurosensory outcomes. Given the evidence of both benefits and harms of treatment, and the limitations of the evidence at present, it appears prudent to reserve the use of late corticosteroids to infants who cannot be weaned from mechanical ventilation and to minimise the dose and duration of any course of treatment.