Aerosol drug delivery to spontaneously-breathing preterm neonates: lessons learned

Abstract

Delivery of medications to preterm neonates receiving non-invasive ventilation (NIV) represents one of the most challenging scenarios for aerosol medicine. This challenge is highlighted by the undersized anatomy and the complex (patho)physiological characteristics of the lungs in such infants. Key physiological restraints include low lung volumes, low compliance, and irregular respiratory rates, which significantly reduce lung deposition. Such factors are inherent to premature birth and thus can be regarded to as the intrinsic factors that affect lung deposition. However, there are a number of extrinsic factors that also impact lung deposition: such factors include the choice of aerosol generator and its configuration within the ventilation circuit, the drug formulation, the aerosol particle size distribution, the choice of NIV type, and the patient interface between the delivery system and the patient. Together, these extrinsic factors provide an opportunity to optimize the lung deposition of therapeutic aerosols and, ultimately, the efficacy of the therapy.In this review, we first provide a comprehensive characterization of both the intrinsic and extrinsic factors affecting lung deposition in premature infants, followed by a revision of the clinical attempts to deliver therapeutic aerosols to premature neonates during NIV, which are almost exclusively related to the non-invasive delivery of surfactant aerosols. In this review, we provide clues to the interpretation of existing experimental and clinical data on neonatal aerosol delivery and we also describe a frame of measurable variables and available tools, including in vitro and in vivo models, that should be considered when developing a drug for inhalation in this important but under-served patient population.

The Miracles of Surfactant: Less Invasive Surfactant Administration, Nebulization, and Carrier of Topical Drugs

“…Clinical data are still scarce. In total, 3 pilot studies [58,60,69], a phase 1 clinical study [59] and a subsequent phase 2 clinical trial [70], and 4 RCTs have been published, comprising an overall number of 909 preterm infants (Table 2) [57,59,71,72]. While all studies documented feasibility and safety, inconsistent results were found concerning efficacy.…”

“…Given that aerosol groups were compared to historical controls, however, conclusion about efficacy is limited [70]. Very recently, a multicenter RCT in 129 infants with mild-to-moderate RDS compared nCPAP with 2 different dosing regimens of nebulized surfactant with nCPAP alone [72]. The authors found no reduction in the likelihood of respiratory failure within the first 72 h of life, and the trial was stopped early due to limited effect of the intervention [72].…”

“…Very recently, a multicenter RCT in 129 infants with mild-to-moderate RDS compared nCPAP with 2 different dosing regimens of nebulized surfactant with nCPAP alone [72]. The authors found no reduction in the likelihood of respiratory failure within the first 72 h of life, and the trial was stopped early due to limited effect of the intervention [72]. It is of interest that the same study group had demonstrated efficacy of aerosolized surfactant in preclinical settings before [68].…”

Breath-Triggered Drug Release System for Preterm Neonates

“…Furthermore, there is the approach of standard aerosolizers, such as the Aerogen ® (Aerogen Ltd., Galway, Ireland), to synchronize aerosol production with breathing, feeding the aerosol into the inhalation limb. However, since the distance from the nebulizer to the patient is large, respiration-synchronized aerosol delivery is not possible due to the considerable delay before the aerosol reaches the patient [ 25 ].…”

“…It has been shown that for the highest possible inhaled aerosol efficiency the aerosol must also be administered as close as possible to the patient interface [ 25 ]. The greater the distance between the release of the aerosol into the patient interface, the less efficient the delivery due to the longer aerosol path length and thus increased deposition on the walls and a delay in aerosol arrival [ 1 , 26 , 27 , 28 ].…”