Systemic hydrocortisone to prevent bronchopulmonary dysplasia in preterm infants (the SToP-BPD study); a multicenter randomized placebo controlled trial

<p>Abstract</p> <p>Background</p> <p>Randomized controlled trials have shown that treatment of chronically ventilated preterm infants after the first week of life with dexamethasone reduces the incidence of the combined outcome death or bronchopulmonary dysplasia (BPD). However, there are concerns that dexamethasone may increase the risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. So far no randomized controlled trial has investigated its efficacy when administered after the first week of life to ventilated preterm infants.</p> <p>Methods/Design</p> <p>The SToP-BPD trial is a randomized double blind placebo controlled multicenter study including 400 very low birth weight infants (gestational age < 30 weeks and/or birth weight < 1250 grams), who are ventilator dependent at a postnatal age of 7 - 14 days. Hydrocortisone (cumulative dose 72.5 mg/kg) or placebo is administered during a 22 day tapering schedule. Primary outcome measure is the combined outcome mortality or BPD at 36 weeks postmenstrual age. Secondary outcomes are short term effects on the pulmonary condition, adverse effects during hospitalization, and long-term neurodevelopmental sequelae assessed at 2 years corrected gestational age. Analysis will be on an intention to treat basis.</p> <p>Discussion</p> <p>This trial will determine the efficacy and safety of postnatal hydrocortisone administration at a moderately early postnatal onset compared to placebo for the reduction of the combined outcome mortality and BPD at 36 weeks postmenstrual age in ventilator dependent preterm infants.</p> <p>Trial registration number</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2768">NTR2768</a></p

Incidence of hypo- and hyper-capnia in a cross-sectional European cohort of ventilated newborn infants

To determine the incidence of hypo- and hyper-capnia in a European cohort of ventilated newborn infants

Open-label glucocorticoids modulate dexamethasone trial results in preterm infants

CONTEXT: Open-label glucocorticoids (OLGs) were often used in trials that investigated postnatal dexamethasone treatment in ventilated preterm infants. OBJECTIVE: To determine if OLG use modulates the dexamethasone treatment effect on mortality, bronchopulmonary dysplasia (BPD), and neurodevelopmental outcome. METHODS: Electronic databases, abstracts from the Pediatric Academic Societies, and results of manual reference searches were used as data sources. Fifteen randomized controlled trials comparing dexamethasone with placebo in 721 ventilated preterm infants older than 7 days were identified. The interaction between dexamethasone treatment effect and OLG use was assessed by meta-regression analysis and subgroup meta-analysis according to the percentage of OLG use in the placebo group. Trials with a moderately early (7- to 14-day) or delayed (>3-week) treatment onset were analyzed separately. RESULTS: Moderately early, but not delayed, dexamethasone treatment significantly reduced mortality rates in trials with OLG use at <30% in the placebo arm. Meta-regression analysis revealed that this reduction was inversely related to OLG use. Increasing OLG use strengthened the positive effect of dexamethasone on BPD in the moderately early trials but attenuated the effect in the delayed-treatment trials. In trials with <30% OLG use, dexamethasone increased the risk for cerebral palsy in the delayed, but not the moderately early, treatment trials. CONCLUSIONS: When OLG use is taken into account moderately early dexamethasone treatment reduced mortality rates and the combined outcome mortality and BPD without increasing the risk of adverse neurodevelopmental outcome in ventilated preterm infants. A large randomized controlled trial is needed to confirm or refute these finding

Finding the Optimal Postnatal Dexamethasone Regimen for Preterm Infants at Risk of Bronchopulmonary Dysplasia: A Systematic Review of Placebo-Controlled Trials

CONTEXT. Postnatal dexamethasone therapy reduces the incidence of bronchopulmonary dysplasia in preterm infants but may be associated with an increased risk for adverse neurodevelopmental outcome. OBJECTIVE. Our goal was to determine if the effects of dexamethasone on mortality and pulmonary and neurodevelopmental sequelae in preterm infants are modified by the cumulative dose given. METHODS. Randomized, controlled trials comparing dexamethasone with placebo in ventilated preterm infants >7 days old were identified by searching the electronic databases and the abstracts from the Pediatric Academic societies and by performing manual reference searches. Two reviewers independently assessed eligibility and quality of trials and extracted data on study design, patient characteristics, and relevant outcomes. Original trialists were asked to provide additional data. RESULTS. Sixteen trials including 1136 patients were analyzed by using meta-analysis and metaregression. Additional data were provided by 12 original trialists. Trials with a moderately early (7- to 14-day) or delayed (>3-week) postnatal treatment onset were analyzed separately. Higher dexamethasone doses reduced the relative risk for the combined outcome, mortality or bronchopulmonary dysplasia, with the largest effect in trials that used a cumulative dose of >4 mg/kg. No effect was found of doses on the risk of neurodevelopmental sequelae in the delayed treatment studies, but in the moderately-early-treatment studies the risk of mortality or cerebral palsy decreased by 6.2%, and the risk of a Mental Developmental Index below -2 SDs decreased by 6.6% for each incremental mg/kg cumulative dexamethasone dose. CONCLUSIONS. Higher cumulative dexamethasone doses administered after the first week of life may decrease the risk for bronchopulmonary dysplasia without increasing the risk for neurodevelopmental sequelae in ventilated preterm infants. A large randomized trial is needed to confirm or refute these findings. Pediatrics 2009;123:367-37

Effects of higher versus lower dexamethasone doses on pulmonary and neurodevelopmental sequelae in preterm infants at risk for chronic lung disease: a meta-analysis

OBJECTIVES: Systemic postnatal dexamethasone treatment reduces the risk of chronic lung disease in preterm infants but also may be associated with increased risk of neurodevelopmental impairment. Because it is not known whether these effects are modulated by the cumulative dexamethasone dose, we systematically reviewed the available randomized evidence on the effects of lower versus higher cumulative dexamethasone doses, in terms of death, pulmonary morbidity, and neurodevelopmental outcomes, in preterm infants. METHODS: Randomized, controlled trials comparing higher- versus lower-dosage dexamethasone regimens in ventilated preterm infants were identified by searching the main electronic databases, references from relevant studies, and abstracts from the Societies for Pediatric Research (from 1990 onward). Eligibility and quality of trials were assessed, and data on study design, patient characteristics, and relevant outcomes were extracted. RESULTS: Six studies that enrolled a total of 209 participants were included; 2 studies contrasted cumulative dexamethasone doses in the higher ranges (>2.7 mg/kg in the higher-dosage regimen) and 4 in the lower ranges ( <or=2.7 mg/kg in the higher-dosage regimen). Meta-analysis revealed no effect of dexamethasone dose on rates of death and neurodevelopmental sequelae in these 2 subgroups. Subgroup analysis of the studies contrasting dexamethasone doses in the higher ranges showed that the higher dose of dexamethasone was more effective in reducing the occurrence of chronic lung disease than was the lower dose. Interpretation of these data was hampered by the small samples of randomly assigned children, heterogeneity of study populations and designs, use of late rescue glucocorticoids, and lack of long-term neurodevelopmental data in some studies. CONCLUSIONS: Recommendations for optimal dexamethasone doses for preterm infants at risk for chronic lung disease cannot be based on current evidence. A well-designed, large, randomized, controlled trial is urgently needed to establish the optimal dexamethasone dosage regime

Systemic corticosteroid regimens for prevention of bronchopulmonary dysplasia in preterm infants

Cochrane systematic reviews show that systemic postnatal corticosteroids reduce the risk of bronchopulmonary dysplasia (BPD) in preterm infants. However, corticosteroids have also been associated with an increased risk of neurodevelopmental impairment. It is unknown whether these beneficial and adverse effects are modulated by differences in corticosteroid treatment regimens. To assess the effects of different corticosteroid treatment regimens on mortality, pulmonary morbidity, and neurodevelopmental outcome in very low birth weight (VLBW) infants. We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) in the Cochrane Library (searched 21 March 2016), MEDLINE via PubMed (1966 to 21 March 2016), Embase (1980 to 21 March 2016), and CINAHL (1982 to 21 March 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials. Randomized controlled trials (RCTs) comparing two or more different treatment regimens of systemic postnatal corticosteroids in preterm infants at risk for BPD, as defined by the original trialists. Studies investigating one treatment regimen of systemic corticosteroids to a placebo or studies using inhalation corticosteroids were excluded. Two authors independently assessed eligibility and quality of trials and extracted data on study design, participant characteristics and the relevant outcomes. We asked the original investigators to verify if data extraction was correct and, if possible, to provide any missing data. The primary outcomes to be assessed were: mortality at 36 weeks' postmenstrual age (PMA) or at hospital discharge; BPD defined as oxygen dependency at 36 weeks' PMA; long-term neurodevelopmental sequelae, including cerebral palsy, measured by the Bayley Mental Developmental Index (MDI); and blindness or poor vision. Secondary outcomes were: duration of mechanical ventilation and failure to extubate at day 3 and 7 after initiating therapy; rescue treatment with corticosteroids outside the study period; and the incidence of hypertension, sepsis and hyperglycemia during hospitalizations. Data were analyzed using Review Manager 5 (RevMan 5). We used the GRADE approach to assess the quality of evidence. Fourteen studies were included in this review. Only RCTs investigating dexamethasone were identified. Eight studies enrolling a total of 303 participants investigated the cumulative dosage administered; three studies contrasted a high versus a moderate and five studies a moderate versus a low cumulative dexamethasone dose.Analysis of the studies investigating a moderate dexamethasone dose versus a high-dosage regimen showed an increased risk of BPD (typical risk ratio (RR) 1.50, 95% confidence interval (CI) 1.01 to 2.22; typical risk difference (RD) 0.26, 95% CI 0.03 to 0.49; number needed to treat for an additional harmful outcome (NNTH) 4, 95% CI 1.9 to 23.3; I^2 = 0%, 2 studies, 55 infants) as well as an increased risk of abnormal neurodevelopmental outcome (typical RR 8.33, 95% CI 1.63 to 42.48; RD 0.30, 95% CI 0.14 to 0.46; NNTH 4, 95% CI 2.2 to 7.3; I^2 = 68%, 2 studies, 74 infants) when using a moderate cumulative-dosage regimen. The composite outcomes of death or BPD and death or abnormal neurodevelopmental outcome showed similar results although the former only reached borderline significance.There were no differences in outcomes between a moderate- and a low-dosage regimen.Four other studies enrolling 762 infants investigated early initiation of dexamethasone therapy versus a moderately early or delayed initiation and showed no significant differences in the primary outcomes. The two RCTs investigating a continuous versus a pulse dexamethasone regimen showed an increased risk of the combined outcome death or BPD when using the pulse therapy. Finally, two trials investigating a standard regimen versus a participant-individualized course of dexamethasone showed no difference in the primary outcome and long-term neurodevelopmental outcomes.The quality of evidence for all comparisons discussed above was assessed as low or very low, because the validity of all comparisons is hampered by small samples of randomized infants, heterogeneity in study population and design, non-protocolized use of 'rescue' corticosteroids and lack of long-term neurodevelopmental data in most studies. Despite the fact that some studies reported a modulating effect of treatment regimens in favor of higher-dosage regimens on the incidence of BPD and neurodevelopmental impairment, recommendations on the optimal type of corticosteroid, the optimal dosage, or the optimal timing of initiation for the prevention of BPD in preterm infants cannot be made based on current level of evidence. A well-designed large RCT is urgently needed to establish the optimal systemic postnatal corticosteroid dosage regime

Early prediction of nasal continuous positive airway pressure failure in preterm infants less than 30 weeks gestation

Aim: To predict early nasal continuous positive airway pressure failure within the first 2 h after birth in preterm infants. Methods: Patient and respiratory support variables significantly associated with continuous positive airway pressure failure in the first 72 h after birth were identified in a cohort of preterm infants 0.25 at 1 and 2 h of age were significantly associated with early nasal continuous positive airway pressure failure. Combining these variables in a logistic regression model provided a minimal risk estimate for failure of 0.04[0.01-0.23] (female >800 g, FiO(2) 0.25 at 1 and 2 h). Conclusion: Combining gender, birth weight and the fraction of inspired oxygen at 1 and 2 h of age allows for a better and more individualized prediction of early nasal continuous positive airway pressure failure in preterm infants less than 30 weeks gestatio