(9R)-9-chloro-11-17-dihydroxy-17-(2-hydroxy-1-oxoethyl)-10-13-16-trimethyl-6-7-8-11-12-14-15-16-octahydrocyclopenta[a]phenanthren-3-one and Bronchopulmonary-Dysplasia

Bronchopulmonary dysplasia (BPD), defined as oxygen dependence at 36 weeks postmenstrual age (PMA), remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD. Attenuating pulmonary inflammation with postnatal systemic corticosteroids reduces the incidence of BPD in preterm infants but may be associated with an increased risk of adverse neurodevelopmental outcomes. Local administration of corticosteroids via inhalation might be an effective and safe alternative.. To determine if administration of inhalation corticosteroids after the first week of life until 36 weeks PMA to preterm infants at high risk of developing BPD is effective and safe in reducing the incidence of death and BPD as separate or combined outcomes.. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 4), MEDLINE via PubMed (1966 to 19 May 2017), Embase (1980 to 19 May 2017), and CINAHL (1982 to 19 May 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.. We included randomised controlled trials comparing inhalation corticosteroids, started ≥ 7 days postnatal age (PNA) but before 36 weeks PMA, to placebo in ventilated and non-ventilated infants at risk of BPD. We excluded trials investigating systemic corticosteroids versus inhalation corticosteroids.. We collected data on participant characteristics, trial methodology, and inhalation regimens. The primary outcome was death or BPD at 36 weeks PMA. Secondary outcomes were the combined outcome death or BPD at 28 days PNA, the seperate outcomes of death and BPD at both 28 days PNA, and at 36 weeks PMA, and short-term respiratory outcomes, such as failure to extubate; total days of mechanical ventilation and oxygen use; and the need for systemic corticosteroids. We contacted the original trialists to verify the validity of extracted data and to provide missing data. We analysed all data using Review Manager 5. When possible, we performed meta-analysis using typical risk ratio (RR) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes along with their 95% confidence intervals (CI). We analysed ventilated and non-ventilated participants separately.We used the GRADE approach to assess the quality of the evidence.. We included eight trials randomising 232 preterm infants in this review. Inhalation corticosteroids did not reduce the separate or combined outcomes of death or BPD. The meta-analyses of the studies showed a reduced risk in favor of inhalation steroids regarding failure to extubate at seven days (typical RR (TRR) 0.80, 95% CI 0.66 to 0.98; 5 studies, 79 infants) and at the latest reported time point after treatment onset (TRR 0.60, 95% CI 0.45 to 0.80; 6 studies, 90 infants). However, both analyses showed increased statistical heterogeneity (I. 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.

Topics: Administration, Inhalation; Anti-Inflammatory Agents; Beclomethasone; Bronchopulmonary Dysplasia; Budesonide; Dexamethasone; Fluocinolone Acetonide; Fluticasone; Glucocorticoids; Humans; Infant, Newborn; Infant, Premature; Pneumonia; Randomized Controlled Trials as Topic

This is an update of a review published in 2012. A related review "Inhaled versus systemic corticosteroids for preventing bronchopulmonary dysplasia in ventilated very low birth weight preterm neonates" has been updated as well. Bronchopulmonary dysplasia (BPD) is a serious and common problem among very low birth weight infants, despite the use of antenatal steroids and postnatal surfactant therapy to decrease the incidence and severity of respiratory distress syndrome. Due to their anti-inflammatory properties, corticosteroids have been widely used to treat or prevent BPD. However, the use of systemic steroids has been associated with serious short- and long-term adverse effects. Administration of corticosteroids topically through the respiratory tract may result in beneficial effects on the pulmonary system with fewer undesirable systemic side effects.. To compare the effectiveness of inhaled versus systemic corticosteroids administered to ventilator-dependent preterm neonates with birth weight ≤ 1500 g or gestational age ≤ 32 weeks after 7 days of life on the incidence of death or BPD at 36 weeks' postmenstrual age.. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 1), MEDLINE via PubMed (1966 to 23 February 2017), Embase (1980 to 23 February 2017), and CINAHL (1982 to 23 February 2017). We also searched clinical trials registers, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.. Randomised or quasi-randomised controlled trials comparing inhaled versus systemic corticosteroid therapy (irrespective of dose and duration) starting after the first week of life in ventilator-dependent very low birth weight infants.. We used standard methodological procedures expected by the Cochrane Collaboration.. We included three trials that involved a total of 431 participants which compared inhaled versus systemic corticosteroids to treat BPD. No new trials were included for the 2017 update.Although one study randomised infants at < 72 hours (N = 292), treatment started when infants were aged > 15 days. In this larger study, deaths were included from the point of randomisation and before treatment started. Two studies (N = 139) randomised and started treatment at 12 to 21 days.Two trials reported non-significant differences between groups for the primary outcome: incidence of death or BPD at 36 weeks' postmenstrual age among all randomised infants. Estimates for the largest trial were Relative risk (RR) 1.04 (95% Confidence interval (CI) 0.86 to 1.26), Risk difference (RD) 0.03 (95% CI -0.09 to 0.15); (moderate-quality evidence). Estimates for the other trial reporting the primary outcome were RR 0.94 (95% CI 0.83 to 1.05), RD -0.06 (95% CI -0.17 to 0.05); (low-quality evidence).Secondary outcomes that included data from all three trials showed no significant differences in the duration of mechanical ventilation or supplemental oxygen, length of hospital stay, or the incidence of hyperglycaemia, hypertension, necrotising enterocolitis, gastrointestinal bleed, retinopathy of prematurity or culture-proven sepsis moderate- to low-quality evidence).In a subset of 75 surviving infants who were enrolled from the United Kingdom and Ireland, there were no significant differences in developmental outcomes at seven years of age between groups (moderate-quality evidence). One study received grant support and the industry provided aerochambers and metered dose inhalers of budesonide and placebo for the same study. No conflict of interest was identified.. We found no evidence that inhaled corticosteroids confer net advantages over systemic corticosteroids in the management of ventilator-dependent preterm infants. There was no evidence of difference in effectiveness or adverse event profiles for inhaled versus systemic steroids.A better delivery system guaranteeing selective delivery of inhaled steroids to the alveoli might result in beneficial clinical effects without increasing adverse events.To resolve this issue, studies are needed to identify the risk/benefit ratio of different delivery techniques and dosing schedules for administration of these medications. The long-term effects of inhaled steroids, with particular attention to neurodevelopmental outcomes, should be addressed in future studies.

Topics: Administration, Inhalation; Beclomethasone; Bronchopulmonary Dysplasia; Chronic Disease; Dexamethasone; Glucocorticoids; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Randomized Controlled Trials as Topic; Respiration, Artificial; Respiratory System Agents

Bronchopulmonary dysplasia (BPD) remains an important cause of mortality and morbidity in preterm infants and inflammation plays a significant role in its pathogenesis. The use of inhaled corticosteroids may modulate the inflammatory process without concomitant high systemic steroid concentrations and less risk of adverse effects. This is an update of a review published in 2012 (Shah 2012). We recently updated the related review on "Inhaled versus systemic corticosteroids for treating bronchopulmonary dysplasia in ventilated very low birth weight preterm neonates".. To determine the effect of inhaled versus systemic corticosteroids started within the first 7 days of life on preventing death or BPD in ventilated very low birth weight infants.. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 1), MEDLINE via PubMed (1966 to 23 February 2017), Embase (1980 to 23 February 2017), and CINAHL (1982 to 23 February 2017). We searched clinical trials registers, conference proceedings and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials.. Randomised or quasi-randomised controlled trials comparing inhaled versus systemic corticosteroid therapy (irrespective of dose and duration) starting in the first seven days of life in very low birth weight preterm infants receiving assisted ventilation.. Clinical outcomes data were extracted and analysed using Review Manager. When appropriate, meta-analysis was performed using typical relative risk (RR), typical risk difference (RD) and weighted mean difference (WMD). Meta-analyses were performed using typical relative risk, typical risk difference (RD), and weighted mean difference with their 95% confidence intervals (CI). If RD was statistically significant, the number needed to benefit or the number needed to harm was calculated. We assessed the quality of evidence was evaluated using GRADE principles.. We included two trials that involved 294 infants. No new studies were included for the 2017 update. The incidence of death or BPD at 36 weeks' postmenstrual age was not statistically significantly different between infants who received inhaled or systemic steroids (RR 1.09, 95% CI 0.88 to 1.35; RD 0.05, 95% CI -0.07 to 0.16; 1 trial, N = 278). The incidence of BPD at 36 weeks' postmenstrual age among survivors was not statistically significant between groups (RR 1.34, 95% CI 0.94 to 1.90; RD 0.11, 95% CI -0.02 to 0.24; 1 trial, N = 206). There was no statistically significant difference in the outcomes of BPD at 28 days, death at 28 days or 36 weeks' postmenstrual age and the combined outcome of death or BPD by 28 days between groups (2 trials, N = 294). The duration of mechanical ventilation was significantly longer in the inhaled steroid group compared with the systemic steroid group (typical MD 4 days, 95% CI 0.2 to 8; 2 trials, N = 294; I² = 0%) as was the duration of supplemental oxygen (typical MD 11 days, 95% CI 2 to 20; 2 trials, N = 294; I² = 33%).The incidence of hyperglycaemia was significantly lower with inhaled steroids (RR 0.52, 95% CI 0.39 to 0.71; RD -0.25, 95% CI -0.37 to -0.14; 1 trial, N = 278; NNTB 4, 95% CI 3 to 7 to avoid 1 infant experiencing hyperglycaemia). The rate of patent ductus arteriosus increased in the group receiving inhaled steroids (RR 1.64, 95% CI 1.23 to 2.17; RD 0.21, 95% CI 0.10 to 0.33; 1 trial, N = 278; NNTH 5, 95% CI 3 to 10). In a subset of surviving infants in the United Kingdom and Ireland there were no significant differences in developmental outcomes at 7 years of age. However, there was a reduced risk of having ever been diagnosed as asthmatic by 7 years of age in the inhaled steroid group compared with the systemic steroid group (N = 48) (RR 0.42, 95% CI 0.19 to 0.94; RD -0.31, 95% CI -0.58 to -0.05; NNTB 3, 95% CI 2 to 20).According to GRADE the quality of the evidence was moderate to low. Evidence was downgraded on the basis of design (risk of bias), consistency (heterogeneity) and precision of the estimates.Both studies received grant support and the industry provided aero chambers and metered dose inhalers of budesonide and placebo for the larger study. No conflict of interest was identified.. We found no evidence that early inhaled steroids confer important advantages over systemic steroids in the management of ventilator-dependent preterm infants. Based on this review inhaled steroids cannot be recommended over systemic steroids as a part of standard practice for ventilated preterm infants. Because they might have fewer adverse effects than systemic steroids, further randomised controlled trials of inhaled steroids are needed that address risk/benefit ratio of different delivery techniques, dosing schedules and long-term effects, with particular attention to neurodevelopmental outcome.

Topics: Administration, Inhalation; Anti-Inflammatory Agents; Beclomethasone; Bronchopulmonary Dysplasia; Budesonide; Chronic Disease; Dexamethasone; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Randomized Controlled Trials as Topic; Respiration, Artificial; Respiratory System Agents; Steroids

Bronchopulmonary dysplasia (BPD), defined as oxygen dependence at 36 weeks postmenstrual age (PMA), remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD. Attenuating pulmonary inflammation with postnatal systemic corticosteroids reduces the incidence of BPD in preterm infants but may be associated with an increased risk of adverse neurodevelopmental outcomes. Local administration of corticosteroids via inhalation might be an effective and safe alternative.. To determine if administration of inhalation corticosteroids after the first week of life to preterm infants at high risk of developing BPD is effective and safe in reducing the incidence of death and BPD as separate or combined outcomes.. We identified randomised, controlled trials by searching the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), PubMed (from 1966), EMBASE (from 1974), CINAHL (from 1982), references from retrieved trials and handsearches of journals, all assessed to February 2012.. Randomised controlled trials comparing inhalation corticosteroids, started ≥ 7 days postnatal age (PNA) but before 36 weeks PMA, to placebo in ventilated and non-ventilated infants at risk of BPD were included. Trials investigating systemic corticosteroids versus inhalation corticosteroids were excluded.. Data on patient characteristics, trial methodology, and inhalation regimens were collected. The primary outcomes were death or BPD, or both, at 28 days PNA or 36 weeks PMA. Secondary outcomes were short-term respiratory outcomes, such as failure to extubate, total days of mechanical ventilation and oxygen use, and the need for systemic corticosteroids. The original trialists were contacted to verify the validity of extracted data and to provide missing data. All data were analysed using RevMan 5.0.24. When possible, meta-analysis was performed using typical risk ratio (TRR) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes along with their 95% confidence intervals (CI). Ventilated and non-ventilated participants were analysed separately.. Eight trials randomising 232 preterm infants were included in this review. Inhalation corticosteroids did not reduce the separate or combined outcomes of death or BPD. Furthermore, inhalation steroids did not impact short-term respiratory outcomes such as failure to extubate and total duration of mechanical ventilation or oxygen dependency. There was a trend to a reduced use of systemic corticosteroids in favour of inhalation corticosteroids (TRR 0.51; 95% CI 0.26 to 1.00). There was a paucity of data on short-term and long-term adverse effects. These results should be interpreted with caution because the total number of randomised patients is relatively small and most trials differed considerably in patient characteristics, inhalation therapy and outcome definitions.. 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.

Topics: Administration, Inhalation; Androstadienes; Anti-Inflammatory Agents; Beclomethasone; Bronchopulmonary Dysplasia; Budesonide; Dexamethasone; Fluocinolone Acetonide; Fluticasone; Glucocorticoids; Humans; Infant, Newborn; Infant, Premature; Pneumonia; Randomized Controlled Trials as Topic

The efficacy of inhaled steroids in spontaneously breathing infants with established bronchopulmonary dysplasia (BPD) is debatable. The inhaled steroid hydrofluoalkane-beclomethasone dipropionate (QVAR) is unique in its small particle size that results in higher lung deposition. Our objective was to determine if inhaled QVAR could decrease respiratory rehospitalizations of infants with established BPD.. Double-blind, randomized placebo-controlled, multicenter pilot study. Preterm infants with moderate-to-severe BPD were randomized to inhaled QVAR 100 μg per dose or placebo twice daily via Aerochamber with face mask. Treatment was administered daily from recruitment at 36 weeks post menstrual age until 3 months post discharge. Analysis was carried out by intention to treat.. The QVAR (n=18) and placebo (n=20) groups were comparable in birth and recruitment characteristics. Length of stay (108.5±26.3 vs 108.7±36.0 days) and infants requiring oxygen at discharge (5/17 vs 6/19) or at study end (0/17 vs 2/19) were comparable. Respiratory rehospitalizations/infant (0.1±0.5 vs 0.4±0.6), rehospitalization days (0.5±1.5 vs 4.1±10.3), and post-discharge additive inhaled (0.3±0.9 vs 6.4±21.5 days), systemic (0.7±2.8 vs 1.0±1.4 days) and combined (inhaled/systemic) steroids (1.0±2.9 vs 7.8±25.8 days) tended to be lower in the QVAR compared with the placebo group. Blood pressure, height and weight gain, and urine cortisol/creatinine ratio at study end were comparable between groups.. Our study was unable to detect a significant effect of inhaled QVAR on the respiratory course of established BPD. The study was underpowered. Possible benefits of QVAR could be masked by a tendency toward higher use of additional steroids in the placebo group.

Topics: Administration, Inhalation; Beclomethasone; Bronchopulmonary Dysplasia; Double-Blind Method; Female; Glucocorticoids; Humans; Infant; Infant, Extremely Premature; Infant, Newborn; Infant, Very Low Birth Weight; Israel; Length of Stay; Male; Patient Readmission; Pilot Projects; Respiration, Artificial; Treatment Outcome

We tested the hypothesis that inhaled beclomethasone therapy for prevention of bronchopulmonary dysplasia (BPD) reduces pulmonary inflammation. As part of a randomized, placebo-controlled trial, interleukin-8 (IL-8) and interleukin-1 receptor antagonist (IL-1ra) concentrations in tracheal aspirates were measured as markers of pulmonary inflammation. On study days 1 (baseline), 8, 15, and day 28 of age, samples were obtained from enrolled infants (birth weights <1,251 g, gestational age <33 week, 3 to 14 days of age) who remained ventilated and had not received systemic glucocorticoid therapy. Cytokine levels (pg/microg of free secretory component of immunoglobulin A) were compared between groups. We determined whether baseline cytokine levels modified treatment effect regarding subsequent need for systemic glucocorticoid therapy or occurrence of BPD (age 28 days). Tracheal aspirates were obtained from 161 infants (77 receiving beclomethasone, 84 receiving placebo). Median IL-8 levels were lower in beclomethasone versus placebo infants on study days 8 (82.9 vs. 209.2, P < 0.01) and 15 (37.4 vs. 77.4, P < 0.03) after controlling for antenatal glucocorticoid therapy and maternal race. Median IL-1ra levels were lower in beclomethasone versus placebo infants only on study day 8 (86.5 vs. 153.3, P < 0.01). Fewer beclomethasone infants with baseline IL-8 levels in the interquartile range required systemic glucocorticoid therapy (beclomethasone 30.6% vs. placebo 65.8%, P < 0.01) or developed BPD (beclomethasone 42.4% vs. placebo 69.4%, P < 0.03). We conclude that early-inhaled beclomethasone therapy was associated with a reduction in pulmonary inflammation after 1 week of therapy. Beclomethasone-treated infants with moderately elevated baseline IL-8 levels received less subsequent systemic glucocorticoid therapy and had a lower incidence of BPD than nontreated infants.

Topics: Administration, Inhalation; Beclomethasone; Body Fluids; Bronchopulmonary Dysplasia; Female; Glucocorticoids; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Inflammation Mediators; Interleukin-8; Male; Receptors, Interleukin-1; Respiration, Artificial; Trachea

The safety and efficacy of inhaled glucocorticoid therapy for asthma stimulated its use in infants to prevent bronchopulmonary dysplasia. We tested the hypothesis that early therapy with inhaled glucocorticoids would decrease the frequency of bronchopulmonary dysplasia in premature infants.. We conducted a randomized, multicenter trial of inhaled beclomethasone or placebo in 253 infants, 3 to 14 days old, born before 33 weeks of gestation and weighing 1250 g or less at birth, who required ventilation therapy. Beclomethasone was delivered in a decreasing dosage, from 40 to 5 microg per kilogram of body weight per day, for four weeks. The primary outcome measure was bronchopulmonary dysplasia at 28 days of age. Secondary outcomes included bronchopulmonary dysplasia at 36 weeks of postmenstrual age, the need for systemic glucocorticoid therapy, the need for bronchodilator therapy, the duration of respiratory support, and death.. One hundred twenty-three infants received beclomethasone, and 130 received placebo. The frequency of bronchopulmonary dysplasia was similar in the two groups: 43 percent in the beclomethasone group and 45 percent in the placebo group at 28 days of age, and 18 percent in the beclomethasone group and 20 percent in the placebo group at 36 weeks of postmenstrual age. At 28 days of age, fewer infants in the beclomethasone group than in the placebo group were receiving systemic glucocorticoid therapy (relative risk, 0.6; 95 percent confidence interval, 0.4 to 1.0) and mechanical ventilation (relative risk, 0.8; 95 percent confidence interval, 0.6 to 1.0).. Early beclomethasone therapy did not prevent bronchopulmonary dysplasia but was associated with lower rates of use of systemic glucocorticoid therapy and mechanical ventilation.

Topics: Administration, Inhalation; Beclomethasone; Bronchodilator Agents; Bronchopulmonary Dysplasia; Double-Blind Method; Drug Administration Schedule; Female; Glucocorticoids; Humans; Infant, Newborn; Infant, Premature; Male; Oxygen Inhalation Therapy; Respiration, Artificial; Respiratory Distress Syndrome, Newborn

We tested the hypothesis that inhaled beclomethasone therapy for prevention of bronchopulmonary dysplasia does not cause adrenal suppression.. Infants receiving ventilatory support with birth weights

Topics: Administration, Inhalation; Adrenal Glands; Adrenal Insufficiency; Beclomethasone; Bronchopulmonary Dysplasia; Double-Blind Method; Female; Glucocorticoids; Humans; Hydrocortisone; Infant, Newborn; Infant, Premature; Male; Statistics, Nonparametric

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.

Topics: Administration, Inhalation; Albuterol; Beclomethasone; Bronchodilator Agents; Bronchopulmonary Dysplasia; Double-Blind Method; Glucocorticoids; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Logistic Models; Prospective Studies

The object of this study was to examine the hypothesis that meter-dosed, inhaled beclomethasone administered to premature infants beginning at birth in a tapering dosage schedule over the first 12 days of life attenuates bronchoalveolar lining fluid oxyradical inflammation concomitant with modulation of bronchopulmonary dysplasia. The design of this study was an unblinded, uncontrolled phase I, pilot investigation of inhaled beclomethasone primarily examining safety and administration. The setting was a tertiary care neonatal intensive care unit. Intubated, premature infants were studied longitudinally to 36 weeks corrected gestational age. Meter-dosed, inhaled beclomethasone was administered in a tapering dosage schedule over the first 12 days of life. Endotracheal tube aspirates were collected on Days 2, 4, and 6 of life and assayed for various markers of bronchoalveolar lining fluid oxyradical stress. Infants were also assessed with regards to a number of relevant clinical variables and presence or absence of bronchopulmonary dysplasia at 36 weeks corrected gestational age. Although no differences in clinical outcome were apparent in comparing nine control infants with nine beclomethasone-treated infants, bronchoalveolar lining fluid from control infants exhibited evidence of apparent phospholipid peroxidation (enhanced polyunsaturated fatty acid consumption) on Day 2 of life compared to beclomethasone-treated infants. Significant differences were noted for percent arachidonic acid, total polyunsaturated fatty acids and ratio of polyunsaturated fatty acids, to saturated fatty acids. The ratio of monohydroxyl linolenic acid to native linoleic acid (a more specific marker of lipid peroxidation) as well as myeloperoxidase activity (a marker of neutrophil oxyradical stress) tended to be higher in the control group but did not achieve statistical significance for this small subject number study. No adverse reactions related to meter-dosed, inhaled beclomethasone were noted in the treatment group; most specifically no evidence of hypothalamic-pituitary-adrenal axis suppression was noted in either control or beclomethasone-treated infants. Meter-dosed, inhaled beclomethasone in the dosage schedule utilized was safe and appeared to moderate bronchoalveolar lining fluid phospholipid peroxidation. Small numbers of infants entered into the present investigation preclude comments on clinical efficacy because of the likelihood of a statistical type 2 error. However

Topics: Administration, Inhalation; Beclomethasone; Bronchoalveolar Lavage Fluid; Bronchopulmonary Dysplasia; Fatty Acids; Female; Gestational Age; Humans; Hypothalamo-Hypophyseal System; Infant, Newborn; Infant, Premature; Inflammation; Interleukin-8; Lipid Peroxidation; Lung Diseases; Male; Nebulizers and Vaporizers; Peroxidase; Phospholipids; Pilot Projects; Pituitary-Adrenal System; Reactive Oxygen Species; Severity of Illness Index

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.

Topics: Anti-Inflammatory Agents; Bacterial Infections; Beclomethasone; Blood Glucose; Blood Pressure; Body Weight; Bronchopulmonary Dysplasia; Double-Blind Method; Feasibility Studies; Female; Glucocorticoids; Heart Rate; Humans; Hydrocortisone; Infant, Low Birth Weight; Infant, Newborn; Male; Nebulizers and Vaporizers; Oxygen Inhalation Therapy; Placebos; Respiration; Respiratory Distress Syndrome, Newborn; Retinopathy of Prematurity; Safety; Sodium Chloride; Ventilators, Mechanical

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.

Topics: Administration, Inhalation; Airway Resistance; Bacterial Infections; Beclomethasone; Bronchopulmonary Dysplasia; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Lung Compliance; Nebulizers and Vaporizers; Oxygenators; Placebos; Prospective Studies; Tidal Volume; Time Factors; Ventilators, Mechanical

Topics: Adrenal Cortex Hormones; Beclomethasone; Bronchopulmonary Dysplasia; Double-Blind Method; Humans; Infant, Newborn; Pilot Projects

To determine demographic and clinical variables associated with inhaled corticosteroid administration and to evaluate between-hospital variation in inhaled steroid use for infants with bronchopulmonary dysplasia (BPD).. Retrospective Cohort Study.. Neonatal units of 35 US children's hospitals; as recorded in the Pediatric Health Information System (PHIS) database.. 1429 infants with evolving BPD at 28 days who were born at <29 weeks gestation with birth weight <1500 grams, admitted within the first 7 postnatal days, and discharged between January 2007-June 2011.. Inhaled steroids were prescribed to 25% (n = 352) of the cohort with use steadily increasing during the first two months of hospitalization. The most frequently prescribed steroid was beclomethasone (n = 194, 14%), followed by budesonide (n = 125, 9%), and then fluticasone (n = 90, 6%). Birth gestation <24 weeks, birth weight 500-999 grams, and prolonged ventilation all increased the adjusted odds of ever receiving inhaled corticosteroids (p<0.05). Wide variations between hospitals in the frequency of infants ever receiving inhaled steroids (range: 0-60%) and the specific drug prescribed were noted. This variation persisted, even after controlling for observed confounders.. Inhaled corticosteroid administration to infants with BPD is common in neonatal units within U.S. Children's hospitals. However, its utilization varies markedly between centers from no treatment at some institutions to the majority of infants with BPD being treated at others. This supports the need for further research to identify the benefits and potential risks of inhaled steroid usage in infants with BPD.

Topics: Administration, Inhalation; Beclomethasone; Bronchopulmonary Dysplasia; Budesonide; Fluticasone; Glucocorticoids; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Inpatients; Retrospective Studies

The best delivery of a drug in ventilated neonates is obtained when using a small particle diameter solution administered via a spacer. Lung deposition of hydrofluoroalkane beclomethasone dipropionate (QVAR, 1.3 microm particles), delivered via an Aerochamber-MV15, was measured in piglets under conditions mimicking ventilated severely ill neonates (uncuffed 2.5 mm endotracheal tube; peak pressure 16 cm H2O; respiratory rate 40/min). After determining the mass and particle size distribution of the 99mTc-labeled and unlabeled drug, three lung deposition studies were performed: after 1 h of ventilation (controls, n = 18), after 48 h aggressive ventilation inducing an acute lung injury (nine piglets out of the controls), and after increasing the pressure to 24 cm H2O during drug delivery (five piglets out of the nine with acute lung injury). All piglets were then killed for lung histology. Results (median, range), expressed as a percentage of the delivered dose, were compared using an inferential or the Friedman test. While lung deposition was low, it was greater (p = 0.003) in controls (2.66%, 0.50-7.70) than in piglets with histologically confirmed acute lung injury (0.26%, 0.06-1.28) or under a high-pressure ventilation (1.01%, 0.30-2.15). Lung deposition of QVAR in an animal model of ventilated neonates is low, variable, and dramatically affected by lung injury.

Topics: Aerosol Propellants; Animals; Animals, Newborn; Beclomethasone; Bronchopulmonary Dysplasia; Disease Models, Animal; Glucocorticoids; Humans; Hydrocarbons, Fluorinated; Infant, Newborn; Lung; Male; Swine

Topics: Beclomethasone; Bronchopulmonary Dysplasia; Humans; Infant, Newborn; Infant, Premature

The effect of inhaled beclomethasone dipropionate (BEC) was studied in seven infants between 7 and 18 months of age with glucocorticoid-dependent bronchopulmonary dysplasia. Oral glucocorticoid therapy, pulmonary function, growth, daily caloric consumption, blood pressure, blood sugar, blood gases, and immunoglobulins were monitored for 3 months before (control period) and 3 months after (intervention period) instituting inhaled beclomethasone dipropionate (25 micrograms/kg/day divided tid) delivered by Pulmoaide with a DeVilbiss nebulizer. Acute BEC inhalation produced no change in pulmonary function. During BEC treatment, oral glucocorticoid therapy was decreased in all infants, stopped in four infants within 3 months and in the other three infants in 4-5 months. Within 1 month of inhaled BEC the rate of linear growth and weight increased markedly (2.2 +/- 1.8 vs 6.4 +/- 2.4 cm/month - mean +/- SD and 9.3 +/- 6.5 vs 18.2 +/- 7.4 g/day, respectively without change in average daily caloric consumption (113 +/- 16 vs. 110 +/- 15 cal/kg/day). Immunoglobulins also significantly increased during BEC therapy (IgG(Total) 246 +/- 74 vs 463 +/- 111 mg/dL). Pulmonary function revealed moderate obstructive pulmonary disease before BEC. After 3 months of BEC inhalation no significant change occurred although respiratory system resistance decreased and the flow at 25% of tidal volume to peak flow ratio increased more than predicted by intersession variability. In no infant did pulmonary function decline after BEC, nor were any apparent adverse effects noted in this small group of patients. In conclusion, inhaled BEC was effective in decreasing oral glucocorticoid therapy and in modifying glucocorticoid-induced growth suppression in a very small, highly select group of infants with bronchopulmonary dysplasia.

Topics: Administration, Inhalation; Administration, Oral; Aerosols; Beclomethasone; Bronchopulmonary Dysplasia; Female; Humans; Infant; Infant, Newborn; Male; Prednisone; Respiratory Function Tests; Time Factors

Little is known about delivery of aerosolised steroids to neonatal patients undergoing assisted positive pressure ventilation and after extubation. A rabbit model has been established to investigate factors influencing drug delivery. Beclomethasone dipropionate, in a metered dose inhaler, was radiolabelled with technetium 99m. The mass median aerodynamic diameter of the aerosol was 3.3 (2.0) microns and the impactor measurements confirmed that the technetium distribution corresponded with that of the drug particles. The metered dose inhaler was actuated into a collapsible spacer that was used to ventilate and deliver aerosol to anaesthetised rabbits by a tracheostomy. From each actuation of the drug 2.9 (0.4)% of the aerosol deposited in the trachea and main bronchi and 1.2 (0.4)% in the lung. When the drug was delivered by a spacer device, with face-mask attachment, to rabbits breathing freely through a tracheostomy, aerosol deposition increased to 4.4 (2.1)% in the trachea and main bronchi and 1.9 (0.9)% in the lung lobes. The maximum change in systolic blood pressure after administration of aerosol by the collapsible spacer was a decrease of 13%. The methods described may prove useful for the delivery of inhaled steroids to neonatal patients likely to develop bronchopulmonary dysplasia.

Topics: Administration, Inhalation; Aerosols; Animals; Beclomethasone; Bronchopulmonary Dysplasia; Drug Administration Schedule; Evaluation Studies as Topic; Humans; Infant, Newborn; Isotope Labeling; Lung; Models, Biological; Nebulizers and Vaporizers; Pilot Projects; Rabbits

Since systemic dexamethasone therapy for bronchopulmonary dysplasia is associated with numerous side effects, a simple system to deliver aerosolized beclomethasone dipropionate (BDP) directly to the lungs of intubated neonates was developed and evaluated in vitro. The system consists of a self-inflating bag, metered dose inhaler (MDI) adapter, Tygon spacer and endotracheal tube (ETT). A dose is delivered by discharging the MDI into the system and giving 3 'breaths' with the bag. Different sizes of ETT do not affect the drug output (1.17 +/- 0.29 vs. 1.32 +/- 0.34 micrograms of BDP per dose using a 3.0-mm or 3.5-mm ETT, respectively; means +/- SD). However, a shorter system spacer substantially reduces the drug output. The majority (54.0%) of the particles exiting the ETT and available to the patient are in the respirable range (0.5-5.5 microns). Based on adult doses and delivery of BDP and the relative sizes of the adult and neonatal lung, it is estimated that a neonate will require 1-6 doses/day. Replacing dexamethasone in the treatment of bronchopulmonary dysplasia with aerosol topical steroids delivered by this system may improve both the safety and efficacy.

Topics: Aerosols; Beclomethasone; Bronchopulmonary Dysplasia; Equipment Design; Evaluation Studies as Topic; Humans; Infant, Newborn; Particle Size