A Dose-Ranging Study to Assess the Effect of Inhaled Corticosteroids in Ventilated Preterm Neonates
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 41
- 主要终点
- Reduction in FiO2 > 75%
研究概览
简要总结
While many short-term morbidities associated with extreme prematurity have declined over the last two decades, the incidence of bronchopulmonary dysplasia (BPD) has increased to a rate of approximately 45% in neonates <28 weeks gestational age (GA) and birth weight (BW) <1,500 g. Neonates with BPD are at increased risk for adverse short-and long-term neurodevelopmental and respiratory outcomes that often persist into adulthood.
There is a growing body of pathological and biochemical evidence that implicates inflammation in its pathogenesis. This is further supported by randomized controlled trials (RCTs) that demonstrate the efficacy of systemic corticosteroids in facilitating extubation and reducing BPD. However, several short- and long-term adverse effects associated with the use of systemic corticosteroids have been described, the most concerning of which is their effect on neurodevelopment, specifically an increased rate of cerebral palsy (CP).
Inhaled corticosteroids (ICS) are an attractive alternative to systemic steroids because of these concerns. Earlier systematic reviews had not found any benefit in using ICS for the prevention or treatment of BPD. However, a recent systematic review showed a significant reduction in death or BPD at 36 weeks' corrected GA (CGA) (risk ratio=0.86, 95% confidence interval 0.75, 0.99), BPD (RR=0.77, 95% CI 0.65, 0.91), and use of systemic steroids (RR=0.87, 95% CI 0.76, 0.98) in infants treated with ICS.
Despite growing evidence of the effectiveness of ICS for BPD, uncertainty remains over treatment timing, effective dose, and long-term effects. There is also variation in the delivery systems used for delivery of ICS. These concerns continue to be echoed in a recent review by Nelin et al. Given that the long-term neurodevelopmental impact of ICS were unknown at the time of this study and many infants are able to wean from ventilation without steroids, the investigators conducted an escalating-dose ranging study of late ICS (i.e. administered after the first week of life) delivered by a metered dose inhaler (MDI) utilizing a specially designed valved delivery system to determine the minimum effective dose necessary to achieve extubation or reduction in oxygen requirements and the long-term neurodevelopmental impact of increasing doses of ICS.
详细描述
Research Question:
What is the effective dose of inhaled steroids (HFA-BDP) in ventilated preterm infants? Material and Methods Objective: The primary purpose of this study is to determine the optimal dose of inhaled steroids (using HFA-BDP) in ventilated preterm infants. The result from this study will determine the dose of inhaled steroids to be used for a subsequent randomized placebo-controlled trial with sufficient power to determine if inhaled steroid is associated with reduction in CLD in ventilated preterm infants without any detrimental effect on long term neurodevelopmental outcome.
Study Design: Escalating dose-ranging study Study Population: Babies with birth weights < 1,250 grams and gestational age < 32 weeks admitted in the NICU at Sunnybrook and Women's College Health Sciences Centre and Mount Sinai Hospital Inclusion Criteria: Birth weight < 1,250 grams and gestational age < 32 weeks, Need for assisted mechanical ventilation (ventilation rate > 15 breaths/min, and fractional oxygen concentration of inspired gas (Fio2) > 0.3 but < 0.6), Postnatal age 10-21 days, Stable ventilatory requirements over the 48-72 hours prior to enrollment Exclusion Criteria: Actual or suspected sepsis, Congenital cardiorespiratory malformation, Patent ductus arteriosus, Presence of necrotizing enterocolitis, gastrointestinal hemorrhage or perforation, Treatment with systemic dexamethasone Duration of therapy: 7 days Drug Regimen: Groups of neonates will be treated with an escalating dose of HFA-BDP until either efficacy equal to that seen with dexamethasone or significant side-effects are observed. 10 neonates will be treated at each dosage level before moving up to the next dose. Each neonate will be treated with only one dose.
Bowser et al have performed an in vitro evaluation of drug deposition of HFA-BDP (QVAR*) and CPC-BDP MDI (Beclovent) via an aerosol delivery chamber (Aerochamber) and endotracheal tube (uncuffed Portex 3.5, 3.0 and 2.5) at low tidal volumes. The PARI Compas Breath Simulator was used to simulate neonatal and infant respiratory cycles. For both formulations and all endotracheal tubes, the output (*g) increased significantly at the tidal volume and inspiratory flow rates were increased. The 3.5 endotracheal tube side gave greater output/puff at all tidal volumes and for both formulations as compared to the smaller endotracheal tubes. Greater in vitro deposition was measured for QVAR than for beclovent, possibly leading to greater in vivo delivery to the lung of this new HFA-BDP MDI formulation to intubated infants
Thus, for the purpose of this study Beclomethasone Dipropionate (HFA-BDP, QVAR*) in the following doses will be evaluated:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Week 至 4 Weeks（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Birth weight < 1,250 grams
- •Gestational age < 32 weeks
- •Need for assisted, invasive mechanical ventilation with at least the following settings:
- •ventilation rate > 15 breaths per min, fractional oxygen concentration of inspired gas (FiO2) > 30% but < 60%)
- •Postnatal age 10-21 days
- •Stable ventilatory requirements over the 48-72 hours prior to enrollment
排除标准
- •Actual or suspected sepsis
- •Congenital cardiorespiratory malformation
- •Patent ductus arteriosus
- •Presence of necrotizing enterocolitis
- •Presence of gastrointestinal hemorrhage or perforation
- •Treatment with systemic dexamethasone
研究组 & 干预措施
Drug
Patients receiving inhaled beclomethasone diproprionate in four escalating doses:
- 200 mcg bid
- 400 mcg bid
- 600 mcg bid
- 800 mcg bid
干预措施: Inhaled Beclomethasone Dipropionate Monohydrate (Drug)
结局指标
主要结局
Reduction in FiO2 > 75%
时间窗: 1 week per dose
Reduction in FiO2 (%) from the 2 days prior to treatment to the final 2 days of the study period. A reduction in additional FiO2 of 75% or greater will be considered a significant improvement. For example, a baby with a baseline FiO2 of 51% would have a significant reduction in FiO2 if post-treatment FiO2 is less than 0.28 using the following calculation: FiO2 reduction 75% = \[0.21 + 0.25 (0.51-0.21)\]
Successful extubation
时间窗: 1 week per dose
Extubation during the study period is considered to be successful if the infant does not require assisted, invasive ventilation for at least 48 hours after the removal of the endotracheal tube and is extubated during the treatment period.
次要结局
- Peak inspiratory pressure (cm H2O)(1 week)
- Mean airway pressure (cm H2O)(1 week)
- Ventilator rate (breaths per minute)(1 week)
研究者
Vibhuti Shah
Staff Neonatologist
Mount Sinai Hospital, Canada