Gerald C. Smaldone

Background: Aerosol delivery via high flow nasal cannula (HFNC 10-60 L/min) is limited by turbulent losses and leaking at the nose. In theory, a jet nebulizer can utilize the high flow passing through the nebulizer chimney to increase drug delivery, e.g., breath enhanced jet nebulization (BEJN). BEJN was applied to a high flow delivery system and tested in an invitro model compared to conventional mesh nebulizer (VMN). Methods: Aerosol outputs were measured during nebulization of infused ^99mTc/saline which defined maximum aerosol production. Following the output experiments, drug delivery was measured invitro using a model consisting of a HFNC circuit interfaced to a realistic 3D-printed head. Aerosol delivered to the trachea was measured using a shielded ratemeter which defined the rate of drug delivery (µg NaCl/min). ^99mTc/saline was infused at rates of 5 to 60 mL/h for BEJN, 5 to 20 mL/h for VMN with HFNC gas flows of 10 to 60 L/min. Results: BEJN aerosol output increased to a maximum at 50 mL/h, VMN at 12. While 90% of generated particles were lost in the system, maximal drug delivery to the trachea for BEJN was 5 times VMN. BEJN aerosol delivery could be titrated over a wide range of infusion flow rates. At the highest flow of 60 L/min the rate of aerosol delivery ranged over 2 orders of magnitude. Conclusion: Aerosol delivery during HFNC is inefficient. To counteract this effect, BEJN utilizes the high flow in the HFNC to generate increased quantities of aerosol. BEJN delivered a wide range of dose rates at all high flows with delivery tightly controlled by rate of infusion. In the critically ill, BEJN technology may allow titration of bedside dosing by simple adjustment of infusion rate.

BACKGROUND: To understand the fate of aerosols delivered by high-flow nasal cannula using continuous nebulization, an open-source anatomical model was developed and validated with a modified real-time gamma ratemeter technique. Mass balance defined circuit losses. Responsiveness to infusion rate and device technology were tested. METHODS: A nasal airway cast derived from a computed tomography scan was converted to a 3-dimensional–printed head and face structure connected to a piston ventilator (breathing frequency 30 breaths/min, tidal volume 750 mL, duty cycle 0.50). For mass balance experiments, saline mixed with Technetium-99m was infused for 1 h. Aerosol delivery was measured using a gamma ratemeter oriented to an inhaled mass filter at the hypopharynx of the model. Background and dead-space effects were minimized. All components were imaged by scintigraphy. Continuous nebulization was tested at infusion rates of 10–40 mL/h with gas flow of 60 L/min using a breath-enhanced jet nebulizer (BEJN), and a vibrating mesh nebulizer. Drug delivery rates were defined by the slope of ratemeter counts/min (CPM/min) versus time (min). RESULTS: The major source of aerosol loss was at the nasal interface (∼25%). Significant differences in deposition on circuit components were seen between nebulizers. The nebulizer residual was higher for BEJN ( P = .006), and circuit losses, including the humidifier, were higher for vibrating mesh nebulizer ( P = .006). There were no differences in delivery to the filter and head model. For 60 L/min gas flow, as infusion pump flow was increased, the rate of aerosol delivery (CPM/min) increased, for BEJN from 338 to 8,111; for vibrating mesh nebulizer, maximum delivery was 2,828. CONCLUSIONS: The model defined sites of aerosol losses during continuous nebulization and provided a realistic in vitro system for testing aerosol delivery during continuous nebulization. Real-time analysis can quantify effects of multiple changes in variables (nebulizer technology, infusion rate, gas flow, and ventilation) during a given experiment.

Background: In volunteers with idiopathic pulmonary fibrosis (IPF), inhaled Interferon-γ (IFN-γ) is safe and may improve pulmonary function. However, coughing, associated with upper airway deposition, is often reported. To address this problem, a small-particle, breath-enhanced jet nebulizer (i-NEB Mini; InspiRx, Inc., Somerset, NJ) was developed. Using gamma scintigraphy, this device was tested in healthy individuals and subjects with IPF to determine efficiency and regional deposition in lung and airways. Methods: Four healthy individuals and nine subjects with IPF were enrolled. The nebulizer was filled with 2 mL of saline with ^99m Tc bound to diethylenetriaminepentaacetic acid (DTPA) powered continuously with 3.4 L/min of compressed air. Mass median aerodynamic diameter (MMAD) was measured by cascade impactor. To maximize deposition in alveoli, inspiratory flow was limited by an inspiratory resistance incorporated into the nebulizer, resulting in a deep inspiration ∼6 seconds. The treatment was run to completion (10 minutes), and each subject underwent deposition imaging. Mass balance and regions of interest determined upper airway (measured by calibrated stomach activity) and regional lung deposition as a percent of pretreatment nebulizer charge. Results: Subjects tolerated the device with no complaints. MMAD (mean [geometric standard deviation]) = 1.04 [1.92] μm. Lung deposition (mean ± standard error, % nebulizer charge) in healthy subjects was 25.7%±1.72 and in IPF individuals 23.5%±1.59 ( p = 0.604). Upper airway deposition was 1.45% ± 0.786 and 2.3% ± 0.48, respectively ( p = 0.386), and 20.1% was lost during expiration. Central/Peripheral ratios were consistent in both groups, showing high peripheral deposition (1.32 ± 0.050, vs. 1.28 ± 0.046, p = 0.912). Conclusion: The i-NEB Mini jet nebulizer with breath enhancement produced small particles, resulting in minimal upper airway deposition. Using slow and deep breathing, more than half of the emitted dose deposited in the peripheral lung in normal subjects and individuals with IPF. These data indicate that, for future clinical trials, controlled lung doses of small particles, designed to avoid coughing, are possible even in subjects with advanced disease.

BACKGROUND: Inhaled interferon, a potential treatment for idiopathic pulmonary fibrosis, must be formulated with mannitol, which can cause bronchospasm and cough. Coughing during drug inhalation can be affected by many factors, but some factors are fixed by the needs of the formulation and inflammatory disease in the airways. A component of the cough response may be related to sites of deposition, particularly upper and central airways. If deposition sites are important, then manipulating the particle distribution of the aerosol may mitigate coughing. To design a therapeutic formulation and delivery system for formulations that contain mannitol, we tested the effect of particle distribution on cough during mannitol inhalation in volunteers with idiopathic pulmonary fibrosis. METHODS: A solution of mannitol was formulated to match requirements for future interferon formulations (40 mg/mL, 220 mOsm/L). Mannitol aerosols were generated by using different nebulizers providing particle distributions that were expected to vary upper airway deposition. The nebulizer fill volume was adjusted to correct for differences in nebulizer efficiency with a target inhaled mass of 20 mg. Particle distributions were measured by cascade impaction (mass median aerodynamic diameters, 1.2 and 6.5 μm). Seven subjects with idiopathic pulmonary fibrosis participated in the study. To maximize deposition, the subjects were trained to inhale slowly and deeply (6 s inspiration). Spirometry was measured before and after inhalation. The study was carried out on separate days (day 1: 1.2 μm; day 2: 6.5 μm), and the pattern of coughing was observed. RESULTS: Coughing was often spontaneous and provoked by spirometry. When inhaling the 1.2-μm distribution, no subject coughed during inhalation. Six of the seven subjects coughed when inhaling the 6.5-μm particles. Spirometry was unaffected. CONCLUSIONS: In subjects with idiopathic pulmonary fibrosis, nebulized mannitol can cause coughing. Modifying the aerosol distribution prevents coughing during mannitol inhalation. Mannitol aerosols can be inhaled safely without bronchospasm. These data serve to inform future formulation and/or device combinations for planned interferon therapy.

An in-depth review on a new ultrasonic micro-droplet generator which utilizes megahertz (MHz) Faraday waves excited by silicon-based multiple Fourier horn ultrasonic nozzles (MFHUNs) and its potential applications is presented. The new droplet generator has demonstrated capability for producing micro droplets of controllable size and size distribution and desirable throughput at very low electrical drive power. For comparison, the serious deficiencies of current commercial droplet generators (nebulizers) and the other ultrasonic droplet generators explored in recent years are first discussed. The architecture, working principle, simulation, and design of the multiple Fourier horns (MFH) in resonance aimed at the amplified longitudinal vibration amplitude on the end face of nozzle tip, and the fabrication and characterization of the nozzles are then described in detail. Subsequently, a linear theory on the temporal instability of Faraday waves on a liquid layer resting on the planar end face of the MFHUN and the detailed experimental verifications are presented. The linear theory serves to elucidate the dynamics of droplet ejection from the free liquid surface and predict the vibration amplitude onset threshold for droplet ejection and the droplet diameters. A battery-run pocket-size clogging-free integrated micro droplet generator realized using the MFHUN is then described. The subsequent report on the successful nebulization of a variety of commercial pulmonary medicines against common diseases and on the experimental antidote solutions to cyanide poisoning using the new droplet generator serves to support its imminent application to inhalation drug delivery.

Potentially infected individuals (‘source’) are sometimes encouraged to use face masks to reduce exposure of their infectious aerosols to others (‘receiver’). To improve compliance with Respiratory Source Control via face mask and therefore reduce receiver exposure, a mask should be comfortable and effective. We tested a novel face mask designed to improve breathability and filtration using nanofiber filtration. Using radiolabeled test aerosols and a calibrated exposure chamber simulating source to receiver interaction, facepiece function was measured with a life-like ventilated manikin model. Measurements included mask airflow resistance (pressure difference during breathing), filtration, (mask capture of exhaled radiolabeled test aerosols), and exposure (the transfer of ‘infectious’ aerosols from the ‘source’ to a ‘receiver’). Polydisperse aerosols were measured at the source with a mass median aerodynamic diameter of 0.95 µm. Approximately 90% of the particles were 2O] across sealed surgical masks (means: 0.1865 and 0.1791 cmH₂O) approached that of the N95 (mean: 0.2664 cmH₂O). The airflow resistance across the nanofiber face mask whether sealed or not sealed (0.0504 and 0.0311 cmH₂O) was significantly reduced in comparison. In addition, ‘infected’ source airflow filtration and receiver exposure levels for nanofiber face masks placed on the source were comparable to that achieved with N95 placed on the source; 98.98% versus 82.68% and 0.0194 versus 0.0557, respectively. Compared to deflection within and around the conventional face masks, Schlieren optical imaging demonstrated enhanced airflow through the nanofiber mask. Substituting nanofiber for conventional filter media significantly reduced face mask airflow resistance directing more airflow through the face mask resulting in enhanced filtration. Respiratory source control efficacy similar to that achieved through the use of an N95 respirator worn by the source and decreased airflow resistance using nanofiber masks may improve compliance and reduce receiver exposure.

Background: Placing a surgical mask on an infected patient (respiratory source control) may offer a health-care worker (HCW) more protection than donning an N95 respirator (receiver protection). This observation was made in an in vitro study that used hard, nondeformable faces, and the lack of proper N95 fit may have accounted for the observed results. In the present study, we test the effects of fit on respiratory source control protection, using a soft, deformable mannequin head. Methods: Resusci Anne CPR mannequin heads were placed in a chamber allowing 6 air exchanges/hr (14 cubic feet per minute), to simulate an infected patient (source) and an HCW (receiver). The heads were ventilated with a tidal breathing pattern. The source exhaled radioactive aerosols, and a filter was attached to the receiver to quantify inhaled exposure. N95 respirators and surgical masks were tested on both heads. The degree of protection was expressed by calculating the reduction in exposure expressed as a simulated workplace protection factor (sWPF; the ratio of exposure with mask to exposure without mask) compared statistically using confidence intervals. Results: Use of the Resusci Anne heads resulted in improved fit, with higher sWPF than previously reported, for example, for source N95 mask combinations (7,174 vs. 317) as well as receiver (7.53 vs. 1.37). Masks placed on the receiver provided minimal exposure protection (sWPF range 0.99–7.53), except when sealed with Vaseline (sWPF 63.1). Any mask applied to the source mannequin resulted in significant reductions in exposure (sWPF range 214–17,038). Conclusion: Improved fit significantly enhanced the effects of source control protection. A Vaseline-sealed N95 respirator on the receiver offered less protection when compared with any mask on the source. Respiratory source control can offer more protection to HCW and potentially decrease the spread of aerosolized infections.