Effectiveness of budesonide aerosol in ventilator-dependent preterm babies: a preliminary report. Respiratory and systemic effects of inhaled dexamethasone on ventilator dependant preterm infants at risk for bronchopulmonary dysplasia. Inhaled salbutamol and beclomethasone for preventing broncho-pulmonary dysplasia: a randomised double-blind study. Trial of beclomethasone dipropionate by metered-dose inhaler in ventilator-dependent neonates less than 1500 grams. Budesonide delivered by dosimetric jet nebulization to preterm very low birthweight infants at high risk for development of chronic lung disease. Fluticasone inhalation in moderate cases of bronchopulmonary dysplasia. Controlled trial of beclomethasone dipropionate by nebulization in oxygen- and ventilator-dependent infants.
The aim of this randomized, double-blind, placebo-controlled trial was to assess the short-term effect of a topical glucocorticoid (budesonide 600 mu g twice daily) vs. placebo administered by metered dose inhaler (MDL) and spacer (Aerochamber MV15) directly into endotracheal tube of intubated infants for 7 days. Twenty preterm infants (mean birthweight, 1,030 g; mean gestational age, 27.3 weeks)who still needed assisted ventilation at 14 days of age were randomly assigned to receive budesonide (n=9) or placebo (n=11) and completed the study. The primary outcome was the need for mechanical ventilation after 7 days of treatment. Other outcome variables included ventilator settings, blood gases, serum cortisol levels, and bronchoalveolar lavage inflammatory cell counts. No ventilated infant was extubated during the study period. The treatment group showed significant improvements in mean peak inspiratory pressure, ventilator efficiency index, and (A-a) oxygen difference. There were no changes in the placebo group. Serum cortisol levels and bronchoalveolar lavage cell counts did not change significantly during study period. There was no difference in side effects between the groups. This trial demonstrates that topical budesonide administered by MDL and Aerochamber produces clinical improvement in ventilated preterm infants, without glucocorticoid side effects. Short-term inhaled dexamethasone therapy was evaluated in a double blind placebo controlled trial in 36 ventilator dependent preterm neonates (BW < 1500 gm, postnatal age > 7 days) who were at risk for bronchopulmonary dysplasia. Pulmonary and systemic effects were compared at early (day 3), late (7-10 days) and post (14 days after initiation) phases of therapy. Airflow mechanics improved as demonstrated by a net 101% improvement in pulmonary resistance (a decrease from 139 to 101 cm H2O/L/s in the dexamethasone treated infants as compared to an increase from 153 to 267 cmH2O/L/s in the placebo treated infants during the early phase of therapy); this was associated with a 45% increase in inspiratory airflow (1.29 +/- 0.43 to 1.87 +/- 0.978 L/min; p < 0.01), and 37% increase in expiratory airflow. These changes resulted in a significant reduction in the work of breathing such that the mean tidal driving pressure significantly decreased from 13.6 cmH2O to 9.4 cm H2O with inhaled steroid administration. Though the brief duration of therapy did not result in cessation of ventilatory support, the level of support was significantly reduced (decreased values of oxygen supplementation, mean airway pressure and oxygenation index and increased ventilatory efficiency index). The inhaled dexamethasone therapy was also associated with systemic absorption of the drug as evidenced by transient but apparently reversible reduction in serum cortisol levels. No systemic side effects of hypertension, hyperglycemia or nosocomial sepsis were observed. These data demonstrate beneficial effects of short-term inhaled dexamethasone on the resistive airflow properties of preterm infants at risk for BPD and may provide adjunctive means to facilitate weaning in the ventilator dependent neonates. Early inflammatory lesions and bronchial hyperresponsiveness are characteristics of the respiratory distress in premature neonates and are susceptible to aggravation by assisted ventilation. We hypothesized that treatment with inhaled salbutamol and beclomethasone might be of clinical value in the prevention of bronchopulmonary dysplasia (BPD) in ventilator-dependent premature neonates. The study was double-blinded and placebo controlled. We studied 173 infants of less than 31 weeks of gestational age, who needed ventilatory support at the 10th postnatal day. They were randomised to four groups and received either placebo + placebo, placebo + salbutamol, placebo + beclomethasone or beclomethasone + salbutomol, respectively for 28 days. The major criteria for efficacy were: diagnosis of BPD (with score of severity), mortality, duration of ventilatory support and oxygen therapy. The trial groups were similar with respect to age at entry (9.8-10.1 days), gestational age (27.6-27.8 weeks), birth weight and oxygen dependence. We did not observe any significant effect of treatment on survival, diagnosis and severity of BPD, duration of ventilatory support or oxygen therapy. For instance, the odds-ratio (95% confidence interval) for severe or moderate BPD were 1.04 (0.52-2.06) for inhaled beclomethasone and 1.54 (0.78-3.05) for inhaled salbutamol.
                This randomised prospective trial does not support the use of treatment with inhaled beclomethasone, salbutamol or their combination in the prevention of BPD in premature ventilated neonates. Beclomethasone dipropionate administered by metered-dose inhaler to ventilated infants with early chronic lung disease was evaluated in a double-blind, placebo-controlled study to determine the feasibility and safety of administration. Patients selected for study were less than 1500 g birthweight, had previous radiographic evidence of respiratory distress syndrome with early changes of bronchopulmonary dysplasia (BPD), were greater than 2 weeks of age, and had failed attempts at extubation. The metered-dose inhaler was connected to the respirator circuit by an in-line spacer device and either saline placebo or beclomethasone was delivered for 7 days or until extubated. Beclomethasone was delivered in a dose calculated to be approximately 1 mg/kg/day in three divided doses. Nineteen infants were enrolled. Nine received placebo and 10 received beclomethasone. No adverse effects on blood pressure, heart rate, respiratory rate, ventilator settings, concentration or duration of oxygen therapy, incidence of retinopathy of prematurity (ROP) or infections, blood glucose, daily weight, or serum cortisol levels before and after adrenal stimulation tests were observed in the beclomethasone group compared with the placebo group. One infant in the placebo and six infants in the steroid group were extubated during the study period (p = 0.03). These data indicate that beclomethasone dipropionate may be administered safely to intubated neonates without adverse effects of hypertension, hyperglycemia, diminished weight gain, or adrenal suppression frequently seen with systemic steroid administration. Beclomethasone may enhance extubation in infants with early BPD, however, further data are required to substantiate this preliminary observation. We investigated the effect of an aerosolized corticosteroid (budesonide) on the oxygen requirement of infants at high risk for developing chronic lung disease (CLD) in a randomized, double-blind study. The study objective was to attain a 30% decrease in FiO2 levels in the budesonide treatment group after 14 d of therapy. Thirty very low birthweight (VLBW) infants (median (range)) gestational age 26 wk (23-29) and birthweight 805 g (525-1227) were randomized. Inclusion criteria were mechanical ventilation on day 6 of life, or if extubated on nasal continuous positive airway pressure with FiO2 > or = 0.3. The budesonide (Pulmicort) dose was 500 microg bid, or placebo. The aerosol was delivered with a dosimetric jet nebulizer, with variable inspiratory time and breath sensitivity. Inhalations were started on day 7 of life. Twenty-seven patients completed the study. A significant lowering of the FiO2 levels at 21 d of life was not detected. Infants who received budesonide were more often extubated during the study period (7/8 vs 2/9) and had a greater relative change from baseline in their oxygenation index (budesonide decreased 26% vs placebo increased 60%). Subsequent use of intravenous dexamethasone or inhaled budesonide in the treatment group was significantly less. All patients required O2 supplementation on day 28 of life. At 36 wk postconceptual age, 61% of infants in the budesonide group needed supplemental O2 as opposed to 79% in the placebo group. No side effects on growth or adrenal function were observed.
                We conclude that inhaled budesonide aerosol via dosimetric jet nebulizer started on day 7 of life for infants at high risk for developing CLD decreases the need for mechanical ventilation similar to intravenous dexamethasone, but without significant side effects. This randomized, controlled trial was designed to determine the efficacy of inhaled fluticasone propionate on oxygen therapy weaning in a population of preterm infants who were born at <32 weeks of gestation and experienced moderate bronchopulmonary dysplasia (BPD).
                Thirty-two infants who were < or =32 weeks of gestation, had moderate BPD that required supplemental oxygen (fraction of inspired oxygen > or =0.25), and were aged between 28 and 60 days were randomized. Fluticasone propionate 125 microg twice daily for 3 weeks and once daily for a fourth week was delivered to infants who weighed between 500 and 1200 g. The dosage was doubled for infants who weighed > or =1200 g.
                Compared with placebo, treatment had no effect on either duration of supplemental O2 therapy or ventilatory support as assessed by survival analysis. At 28 days, a trend toward a lower cortisol/creatinine ratio in the treatment group was noted compared with placebo (25.1 +/- 18.9 vs 43 +/- 14.4). In the fluticasone group at 28 days, the systolic arterial pressure (78 +/- 3 vs 68 +/- 3 mm Hg) and diastolic arterial pressure (43 +/- 3.4 mm Hg vs 38 +/- 2.0 mm Hg) were higher compared with baseline fluticasone values. The chest radiograph score was lower than baseline (2.8 +/- 1.4 vs 3.7 +/- 2.2) in the fluticasone group at 28 days. This study has a statistical power of 1.0 to detect a significant difference in the duration of oxygen supplementation of >21 days between the study groups.
                We conclude that fluticasone propionate reduces neither supplemental O2 use nor the need for ventilatory support in this patient population. However, fluticasone does have a positive radiologic effect in lowering chest radiograph scores. In addition, our data point to a possible association among inhaled fluticasone treatment and higher arterial blood pressure. Thus, the results of this investigation do not support the use of inhaled corticosteroids in the treatment of oxygen-dependent infants who have established moderate BPD. Parenteral glucocorticoids have been shown to be effective in the treatment of oxygen- and ventilator-dependent bronchopulmonary dysplasia. We conducted a randomized, prospective study using a nebulized, water-soluble form of beclomethasone dipropionate for the treatment of infants with oxygen- and ventilator-dependent lung disease. Newborn infants with chest x-ray changes consistent with bronchopulmonary dysplasia at 14 days of age were randomly assigned, in a paired sequential fashion by birth weight, to treatment (beclomethasone) or placebo (saline solution) groups. Treatment included three nebulized doses of beclomethasone (50 micrograms) or saline solution per day for 28 days. Measured variables included tidal volume, total dynamic compliance, and airway resistance. Weight gain, gender, and incidence of infection during therapy were also recorded. Pulmonary functions were measured before initiation of therapy and weekly thereafter. Thirteen infants, seven in the saline solution group and six in the beclomethasone group, met study criteria and completed treatment. Infants treated with beclomethasone had reductions in airway resistance that were significant in weeks 2, 3, and 4 (p < 0.05, p < 0.02, and p < 0.001, respectively). Dynamic lung compliance increased at weeks 3 and 4 (p < 0.01 and p < 0.05, respectively). As expected, tidal volume increased with weight and time, but there were no significant differences between groups. There were no differences between the groups in weight gain, gender, or infection. This study demonstrates that beclomethasone by nebulization (1) reduced airway resistance in oxygen-dependent neonates with bronchopulmonary dysplasia, (2) improved dynamic lung compliance, as reported with parenterally administered glucocorticoids, and (3) produced no apparent increase in the incidence of infection.
Based on the results of the currently available evidence, inhalation corticosteroids initiated at ≥ 7 days of life for preterm infants at high risk of developing BPD cannot be recommended at this point in time. More and larger randomised, placebo-controlled trials are needed to establish the efficacy and safety of inhalation corticosteroids.