From bench to bedside: in vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy
From bench to bedside: in vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy
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DOI：
10.1186/s12931-019-1096-9
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发表时间：
2019-07-02
影响因子：
5.8
通讯作者：
Salomone, F.
中科院分区：
文献类型：
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作者：
Bianco, F.;Ricci, F.;Salomone, F.
背景：无创输送雾化表面活性剂一直是新生儿学长期追求的目标。然而，雾化表面活性剂的临床疗效仍然没有定论，部分原因是在早产儿肺部沉积雾化药物面临巨大的技术挑战。本研究的目的是研究采用适合新生儿的气雾剂输送策略在体外和体内输送雾化表面活性剂（poractant alfa）的可行性。方法：通过激光衍射测定由定制的 eFlow-Neos 雾化器系统产生的未稀释的 poactant alfa 气雾剂的粒径分布。理论雾化表面活性剂肺剂量是在临床环境复制品中体外估计的，包括新生儿持续气道正压通气 (CPAP) 回路、早产儿上呼吸道模型以及根据患有轻度呼吸窘迫综合征 (RDS) 的婴儿的潮式呼吸模式编程的呼吸模拟器。在 RDS 模型、肺灌洗自主呼吸兔子和经鼻 CPAP 管理的基础上，使用涵盖 100-600 mg/kg 标称剂量范围的雾化表面活性剂进行了剂量反应研究。评估了雾化的猪肺α对动脉气体交换和肺力学的影响。测量肺部外源性肺泡二饱和磷脂酰胆碱（DSPC）作为表面活性剂沉积功效的代表。结果：激光衍射研究表明适合吸入的气溶胶特征（质量中值直径，MMD = 3μm）。体外测定的平均表面活性剂肺剂量为 200 mg/kg 标称剂量的 13.7% +/- 4.0。与仅接受 CPAP 的动物相比，在鼻 CPAP 期间向自主呼吸的兔子输送雾化表面活性剂可显着改善动脉氧合。特别是，用 200 mg/kg 和 400 mg/kg 雾化猪肺阿尔法治疗的动物组在氧合和肺力学方面达到了与用滴注表面活性剂 (200 mg/kg) 治疗的动物组相当的肺部反应。结论：定制的 eFlow-Neos 振动膜雾化器系统有效地产生了可吸入气溶胶 未稀释的poractant alfa。以 200 mg/kg 和 400 mg/kg 剂量递送的雾化表面活性剂引起的肺部反应相当于用 200 mg/kg 气管内表面活性剂推注治疗后观察到的反应。这种具有实验室特征的雾化表面活性剂递送策略目前正在 II 期临床试验中进行评估（EUDRACT 编号：2016-004547-36）。
Background: Non-invasive delivery of nebulized surfactant has been a neonatology long-pursued goal. Nevertheless, the clinical efficacy of nebulized surfactant remains inconclusive, in part, due to the great technical challenges of depositing nebulized drugs in the lungs of preterm infants. The aim of this study was to investigate the feasibility of delivering nebulized surfactant (poractant alfa) in vitro and in vivo with an adapted, neonate-tailored aerosol delivery strategy.Methods: Particle size distribution of undiluted poractant alfa aerosols generated by a customized eFlow-Neos nebulizer system was determined by laser diffraction. The theoretical nebulized surfactant lung dose was estimated in vitro in a clinical setting replica including a neonatal continuous positive airway pressure (CPAP) circuit, a cast of the upper airways of a preterm neonate, and a breath simulator programmed with the tidal breathing pattern of an infant with mild respiratory distress syndrome (RDS). A dose-response study with nebulized surfactant covering the 100-600 mg/kg nominal dose-range was conducted in RDS-modelling, lung-lavaged spontaneously-breathing rabbits managed with nasal CPAP. The effects of nebulized poractant alfa on arterial gas exchange and lung mechanics were assessed. Exogenous alveolar disaturated-phosphatidylcholine (DSPC) in the lungs was measured as a proxy of surfactant deposition efficacy.Results: Laser diffraction studies demonstrated suitable aerosol characteristics for inhalation (mass median diameter, MMD = 3 mu m). The mean surfactant lung dose determined in vitro was 13.7% +/- 4.0 of the 200 mg/kg nominal dose. Nebulized surfactant delivered to spontaneously-breathing rabbits during nasal CPAP significantly improved arterial oxygenation compared to animals receiving CPAP only. Particularly, the groups of animals treated with 200 mg/kg and 400 mg/kg of nebulized poractant alfa achieved an equivalent pulmonary response in terms of oxygenation and lung mechanics as the group of animals treated with instilled surfactant (200 mg/kg).Conclusions: The customized eFlow-Neos vibrating-membrane nebulizer system efficiently generated respirable aerosols of undiluted poractant alfa. Nebulized surfactant delivered at doses of 200 mg/kg and 400 mg/kg elicited a pulmonary response equivalent to that observed after treatment with an intratracheal surfactant bolus of 200 mg/kg. This bench-characterized nebulized surfactant delivery strategy is now under evaluation in Phase II clinical trial (EUDRACT No.:2016-004547-36).