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.

Keywords: Aerosol delivery; Nebulizer; Non-invasive ventilation; Premature infants; Pulmonary drug delivery; Respiratory distress syndrome; Surfactant.

Fig. 1

Differences in the anatomy of the pharynx and larynx of an adult (left) and an infant (right) and their effect on the pathway of aerosol particles (represented by pink dots). Premature infants receive nebulization while lying in a cot or in an incubator (upper panel) whereas nebulization is normally administered to adults with the patient in a seated or erect position (lower panel). Thus, the anatomical differences between adult and neonate are compared for a lying down position in Fig. 1. This graphic highlights the main differences that make the pathway of aerosol particles more curvy in premature infants, potentially reducing the effective delivery of nebulized substance to the lungs.

Fig. 2

Intrinsic and extrinsic factors influencing aerosol drug delivery in premature infants. The figure depicts two possible scenarios: (1) nebulizer positioned in the inspiratory limb of a standard constant flow ventilator (top); this nebulizer positioning could also be applied to bubble Continuous Positive Airway Pressure (CPAP) and variable flow drivers, and to High Flow Nasal Cannula (HFNC); (2) nebulizer positioned between the Y piece and the patient interface in a standard constant flow ventilator (bottom); this nebulizer positioning could be compatible with bubble CPAP but not with variable flow drivers nor HFNC

Fig. 3

a–c Illustrate different types of aerosol generators used to deliver aerosols to spontaneously-breathing premature-infants. Jet or pneumatic nebulizers use compressed gas to break up liquids into aerosols and incorporate baffles to filter large aerosol particles (a). Vibrating-membrane nebulizers consist of a membrane with 1000–7000 laser-drilled holes that vibrate at the top of the liquid reservoir thereby generating a mist of very fine droplets through the holes (b). The capillary aerosol generator (CAG) has been especially designed to deliver synthetic surfactant aerosols; this technology consists of a heated capillary through which surfactant is pumped and further dispersed as an aerosol (c). Medical aerosols usually conform to a log-normal particle size distribution (d); They are usually defined by their Mass Median Aerodynamic Diameter (MMAD) which determines the particle diameter at which half of the aerosolized drug mass lies below and half above the stated diameter. Particle size distribution is usually given as the Mass Median Diameter (MMD), which is not interchangeable with the MMAD. MMD is the output parameter in laser-diffraction experiments and considers the particles to be spherical and of unit density. It should be noted that the MMAD and MMD appear markedly shifted to the right in the distribution compared with the particle diameter mode, median, and mean of the absolute particle counts. a–c adapted from reference [79] and d adapted from reference [70]

Fig. 4

Next Generation Impactor set up and correspondence of the different stages to airway generations

Fig. 5

Classification of non-invasive respiratory support—according to the set parameter (pressure vs. flow). Pressure-controlled modalities are classified further based on the pressure generated (constant flow vs. variable flow). The associated ventilatory modalities are reported for each sub-classification. NIV, non-invasive ventilation; CPAP, continuous positive airway pressure; nCPAP, nasal CPAP; nIPPV, nasal intermittent positive pressure ventilation; HFNC, high flow nasal cannula

Fig. 6

Schematic representation of nebulizer potential position in different NIV systems (a–d) and the effect on the amount of inhalable of drug (E–F). V = valve, that is the element used to produce the pressure when crossed by the flow, P = patient, HUM = humidifier. The dashed line represents the flow of one representative breath. The red line represents the bias flow for a standard mechanical ventilator in proportion to the breathing flow. Pink dots are aerosol particles produced by the nebulizer and dispersed into the flow. Aerosol particles are distributed directly into the bias flow when the nebulizer is placed along the inspiratory limb (e). In contrast, aerosol particles are not removed by the bias flow and are moved only by the breathing flow of the baby when the nebulizer is placed between the patient Y-piece and the airway opening (f). In principle, only the particles that can be inhaled are particles produced by the nebulizer and suspended in the airflow during inspiration. This concept is represented graphically by particles enclosed in inspiration: the concentration of the particles is greater when the nebulizer is placed between the Y piece and the airway opening, compared to when the nebulizer is positioned within the inspiratory limb

Fig. 7

Gamma scintigraphy of newborn piglets obtained after nebulization of 99 m-technetium (^99mTc)-labelled surfactant. These images belong to the recent study conducted by Cunha-Goncalves et al. [130]

Fig. 8

Scheme of an in vitro neonatal circuit for aerosol delivery experiments. The set-up is composed of a neonatal ventilator to provide NIV support followed by a temperature and humidity control unit, a nebulizer placed immediately after the Y-piece, a patient interface (nasal prongs), a cast of the upper airways of a premature neonate (PrINT model), a backup trap to collect the aerosol that impacts in the cast and moves forward as a liquid, drug collecting filters to determine the lung dose and the amount of aerosol reaching the expiratory limb, and a breath simulator programmed with a sinusoidal breathing pattern of a premature neonate. adapted from [182, 184]