Efficiency Of Aerosol Delivery Research Articles

Aerosol Delivery Efficiency With High-Flow Nasal Cannula Therapy in Neonatal, Pediatric, and Adult Nasal Upper-Airway and Lung Models.

High-flow nasal cannula (HFNC) systems employ different methods to provide aerosol to patients. This study compared delivery efficiency, particle size, and regional deposition of aerosolized bronchodilators during HFNC in neonatal, pediatric, and adult upper-airway and lung models between a proximal aerosol adapter and distal aerosol circuit chamber. A filter was connected to the upper airway to a spontaneously breathing lung model. Albuterol was nebulized using the aerosol adapter and circuit at different clinical flow settings. The aerosol mass deposited in the upper airway and lung was quantified. Particle size was measured with a laser diffractometer. Regional deposition was assessed with a gamma camera at each nebulizer location and patient model with minimum flow settings. Inhaled lung doses ranged from 0.2-0.8% for neonates, 0.2-2.2% for the small child, and 0.5-5.2% for the adult models. Neonatal inhaled lung doses were not different between the aerosol circuit and adapter, but the aerosol circuit showed marginally greater lung doses in the pediatric and adult patient models. Impacted aerosols and condensation in the non-heated HFNC and aerosol delivery components contributed to the dispersion of coarse liquid droplets, high deposition (11-44%), and occlusion of the supine neonatal upper airway. In contrast, the upright pediatric and adult upper-airway models had minimal deposition (0.3-7.0%) and high fugitive losses (∼24%) from liquid droplets leaking out of the nose. The high impactive losses in the aerosol adapter (56%) were better contained than in the aerosol circuit, resulting in less cannula sputter (5% vs 22%), fewer fugitive losses (18% vs 24%), and smaller inhaled aerosols (5 µm vs 13 µm). The inhaled lung dose was low (1-5%) during HFNC. Approaches that streamline aerosol delivery are needed to provide safe and effective therapy to patients receiving aerosolized medications with this HFNC system.

Effect of Interrupting Heated Humidification on Nebulized Drug Delivery Efficiency, Temperature, and Absolute Humidity During Mechanical Ventilation: A Multi-Lab In Vitro Study.

Introduction: During mechanical ventilation (MV), inspired gases require heat and humidification. However, such conditions may be associated with reduced aerosol delivery efficiency. The practice of turning off heated humidification before nebulization and the impact of nebulization on humidity in a dry ventilator circuit remain topics of debate. This study aimed to assess the effect of turning off heated humidification on inhaled dose and humidity with nebulizer use during adult MV. Methods: A bronchodilator (albuterol) and two antibiotics (Colistimethate sodium and Amikacin sulfate) were nebulized with a vibrating mesh nebulizer placed at the humidifier inlet and in the inspiratory limb at the Y-piece. Additionally, albuterol was nebulized using a jet nebulizer in both placements. Aerosol particle size distribution was determined through a cascade impactor. Absolute humidity (AH) and temperature of inspired gases were determined with anemometer/hygrometers before, during, and after nebulization, before, during, and up to 60 minutes after interrupting active humidification. Aerosol collected on a filter distal to the endotracheal tube and on impactor stages were eluted and assayed by spectrophotometry. Results: The inhaled dose was greater when both nebulizers were placed at the humidifier inlet than the inspiratory limb at the Y-piece. Irrespective of the nebulizer types and placements, the inhaled dose either decreased or showed no significant change after the humidifier was turned off. The aerosol particle size ranged from 1.1 to 2.7 μm. With interruption of active humidification, humidity of inspired gas quickly dropped below recommended levels, and nebulization in dry ventilator circuit produced an AH between 10 and 20 mgH2O/L, lower than the recommended minimum of 30 mgH2O/L. Conclusion: Interrupting active humidification during MV before nebulization did not improve aerosol delivery efficiency for bronchodilator or antibiotics, but did reduce humidity below recommended levels.

Albuterol Delivery During Invasive Mechanical Ventilation via In-Line Intrapulmonary Percussive Ventilation in a Pediatric Lung Model.

Patients receiving mechanical ventilation often require airway clearance and inhaled therapies. Intrapulmonary percussive ventilation (IPV) combines a high-frequency percussive ventilator with a jet nebulizer. Data on aerosol delivery efficiency of the device are scarce. We evaluated albuterol delivery efficiency while using an IPV in-line adapter under different conditions. A pediatric lung model of invasive mechanical ventilation was used. The following independent variables were evaluated: lung condition (normal vs ARDS), ventilator mode (adaptive pressure ventilation vs pressure control), percent opening of adapter (0% vs 25% vs 50%), IPV driving pressure (25 psi vs 40 psi), IPV percussion setting (easy vs hard), and endotracheal tube (ETT) size (3.5 mm vs 5.5 mm). Albuterol delivery efficiency (mass captured in the filter expressed as percentage of loading dose) was selected as the dependent variable. Albuterol was captured on a filter at the tip of the ETT and quantified via spectrophotometry (276 nm). Albuterol delivery efficiency ranged from 0-2.89%. Median (interquartile range) and 95% CI around the median were 0.54% (0.37-1.00) and 0.50-0.63%, respectively. The coefficient of determination (R2) for the model including all variables was 0.363. The 2 main contributors were percent of adapter opening (R2 0.30) and IPV setting (R2 0.039). Albuterol delivery during invasive mechanical ventilation via in-line IPV in a pediatric lung model was inefficient. Alternative methods of delivering bronchodilators and other inhaled medications should be considered when IPV is used.

729 Aerosol delivery efficiency of nebulizers with and without handheld oscillatory pressure therapy

729 Aerosol delivery efficiency of nebulizers with and without handheld oscillatory pressure therapy

Nebulized fusion inhibitory peptide protects cynomolgus macaques from measles virus infection

Measles is the most contagious airborne viral infection and the leading cause of child death among vaccine-preventable diseases. We show here that aerosolized lipopeptide fusion inhibitor, derived from heptad-repeat regions of the measles virus (MeV) fusion protein, blocks respiratory MeV infection in a non-human primate model, the cynomolgus macaque. We use a custom-designed mesh nebulizer to ensure efficient aerosol delivery of peptide to the respiratory tract and demonstrate the absence of adverse effects and lung pathology in macaques. The nebulized peptide efficiently prevents MeV infection, resulting in the complete absence of MeV RNA, MeV-infected cells, and MeV-specific humoral responses in treated animals. This strategy provides an additional means to fight against respiratory infection in non-vaccinated people, that can be readily translated to human trials. It presents a proof-of-concept for the aerosol delivery of fusion inhibitory peptides to protect against measles and other airborne viruses, including SARS-CoV-2, in case of high-risk exposure.

Position of different nebulizer types for aerosol delivery in an adult model of mechanical ventilation.

BackgroundThe optimal positions of different types of nebulizer for aerosol delivery remain unclear.MethodsThree ICU ventilators employing three types of nebulizer were separately connected to a simulated lung to simulate nebulization during invasive ventilation. Assist/control-pressure control (A/C-PC) mode was utilized, with inspiratory pressure (Pi) set to 12 cmH2O and positive end expiratory pressure (PEEP) set to 5 cmH2O, and with a target Vt of 500 ml. The bias flow of all the ventilators was set to 2 L/min. The three nebulizers were the continuous jet nebulizer (c-JN), the inspiratory synchronized jet nebulizer (i-JN), and the vibrating mesh nebulizer (VMN). The five nebulizer positions were as follows: at the Y-piece (position 1) and 15 cm from the Y-piece (position 2) between the endotracheal tube and the Y-piece, at the Y-piece (position 3) and 15 cm from the Y-piece (position 4) in the inspiratory limb; and at the humidifier inlet (position 5). Aerosols were collected with a disposable filter placed at the simulated lung outlet (n = 3) and were measured by UV spectrophotometry (276 nm). The measurements were compared under different experimental conditions.ResultsThe aerosol delivery of c-JN, i-JN, and VMN was 5.33 ± 0.49~11.12 ± 0.36%, 7.73 ± 0.76~13.75 ± 0.46% and 11.13 ± 56–30.2 ± 1.63%, respectively. The higher aerosol delivery: for c-JN~Positions 2 (10.95 ± 0.15%), fori-JN~Positions 1 or 2 (12.91 ± 0.88% or 13.45 ± 0.42%), for VMN~Positions 4(29.03 ± 1.08%); the lower aerosol delivery: for c-JN~Positions 1, 3 or 5, fori-JN~Positions 4 or 5, for VMN~Positions 5.The highest aerosol delivery:For c-JN at Position 2 (10.95 ± .15%), for i-JN at Position 1 or 2 (12.91 ± .88% or 13.45 ± .42%), for VMN at Positions 4 (29. 03 ± 1.08%); the lower aerosol delivery: for c-JN at Positions 1, 3 or 5, for i-JN at Positions 4 or 5, for VMN at Positions 5. The highest aerosol deliveryof c-JN was lower than that of i-JN while the VMN was the highest (all P < .05). However, no differences were observed between the highest aerosol delivery with c-JN and the lowest aerosol delivery with i-JN. Similar results were found between the lowest aerosol delivery with VMN and the highest aerosol delivery with c-JN /i-JN in the Avea ventilator. There were no differences in the highest aerosol delivery of each nebulizer among the different ventilators (all p > 0.05).ConclusionDuring adult mechanical ventilation, the type and position of nebulizer influences aerosol delivery efficiency, with no differences between ventilators.

Differential Performance and Lung Deposition of Levofloxacin with Different Nebulisers Used in Cystic Fibrosis.

We compared the performance and levofloxacin (Quinsair) lung deposition of three nebulisers commonly used in CF (I-Neb Advance, eFlow rapid, and LC Plus) with the approved nebuliser Zirela. The delivered dose, delivery rate, and aerosol particle size distribution (APSD) for each device were determined using the methods described in the Pharmacopeia. High-resolution computed tomography scans obtained from seven adult patients with mild CF were used to generate computer-aided, three-dimensional models of their airway tree to assess lung deposition using functional respiratory imaging (FRI). The eFlow rapid and the LC Plus showed poor delivery efficiencies due to their high residual volumes. The I-Neb, which only delivers aerosols during the inspiratory phase, achieved the highest aerosol delivery efficiency. However, the I-Neb showed the largest particle size and lowest delivery rate (2.9 mg/min), which were respectively associated with a high extrathoracic deposition and extremely long nebulisation times (>20 min). Zirela showed the best performance considering delivery efficiency (159.6 mg out of a nominal dose of 240 mg), delivery rate (43.5 mg/min), and lung deposition (20% of the nominal dose), requiring less than 5 min to deliver a full dose of levofloxacin. The present study supports the use of drug-specific nebulisers and discourages the off-label use of general-purpose devices with the present levofloxacin formulation since subtherapeutic lung doses and long nebulisation times may compromise treatment efficacy and adherence.

Pulsatile Bi-Directional Aerosol Flow Affects Aerosol Delivery to the Intranasal Olfactory Region: A Patient-Specific Computational Study.

The nasal olfactory region is a potential route for non-invasive delivery of drugs directly from the nasal epithelium to the brain, bypassing the often impermeable blood-brain barrier. However, efficient aerosol delivery to the olfactory region is challenging due to its location in the nose. Here we explore aerosol delivery with bi-directional pulsatile flow conditions for targeted drug delivery to the olfactory region using a computational fluid dynamics (CFD) model on the patient-specific nasal geometry. Aerosols with aerodynamic diameter of 1 µm, which is large enough for delivery of large enough drug doses and yet potentially small enough for non-inertial aerosol deposition due to, e.g., particle diffusion and flow oscillations, is inhaled for 1.98 s through one nostril and exhaled through the other one. The bi-directional aerosol delivery with steady flow rate of 4 L/min results in deposition efficiencies (DEs) of 50.9 and 0.48% in the nasal cavity and olfactory region, respectively. Pulsatile flow with average flow rate of 4 L/min (frequency: 45 Hz) reduces these values to 34.4 and 0.12%, respectively, and it mitigates the non-uniformity of right-left deposition in both the cavity (from 1.77- to 1.33-fold) and the olfactory region (from 624- to 53.2-fold). The average drug dose deposited in the nasal cavity and the olfactory epithelium region is very similar in the right nasal cavity independent of pulsation conditions (inhalation side). In contrast, the local aerosol dose in the olfactory region of the left side is at least 100-fold lower than that in the nasal cavity independent of pulsation condition. Hence, while pulsatile flow reduces the right-left (inhalation-exhalation) imbalance, it is not able to overcome it. However, the inhalation side (even with pulsation) allows for relatively high olfactory epithelium drug doses per area reaching the same level as in the total nasal cavity. Due to the relatively low drug deposition in olfactory region on the exhalation side, this allows either very efficient targeting of the inhalation side, or uniform drug delivery by performing bidirectional flow first from the one and then from the other side of the nose.

Performance of different add-on devices in dual limb non-invasive mechanically ventilated circuit

Aerosol delivery is thought to be improved by giving one or two pMDI puffs before the prescribed nebulizer dose during non-invasive ventilation (NIV). The aim of the present study was to in-vitro evaluate the efficiency of aerosol delivery using newly developed spacers versus standard T-piece in dual limb NIV circuit.Three add-on devices were evaluated: Combihaler, Minimhal, and standard T-piece which were connected to a vibrating mesh nebulizer (VMN), jet nebulizer (JN), or pMDI within NIV circuit. Three experimental setts were evaluated. Firstly, two pMDI puffs were actuated before nebulization of 1 ml of salbutamol respirable solution by VMN using Combihaler, and Minimhal; the second was the actuation of 10 pMDI puffs only without nebulization.; and the third was the nebulization of 1 ml respirable solution by either VMN or JN without the preliminary pMDI puffs. The amount of aerosol deposited on the inhalation filter was quantified by high-performance liquid chromatography.The Combihaler + VMN delivered the highest TID. Aerosol delivery by Combihaler + pMD and Minimhal + pMDI was significantly higher than that of T-piece + pMDI (p = 0.009 and 0.025, respectively). No significant difference was found between the TID of Minimhal + JN and T-piece + JN. No significant effect was found upon using 2 puffs before the nebulized dose with both Minimhal and Combihaler.Combihaler delivered higher aerosol from VMN and pMDI compared to Minimhal, and standard T-piece. Minimhal delivered higher aerosol from pMDI compared to standard T-piece. Introducing two puffs of pMDI before nebulization with both Minimhal and Combihaler insignificantly affected aerosol delivery.

Bronchodilator Delivery via High-Flow Nasal Cannula: A Randomized Controlled Trial to Compare the Effects of Gas Flows.

(1) Background: Aerosol delivery via high-flow nasal cannula (HFNC) has attracted increasing clinical interest. In vitro studies report that the ratio of HFNC gas flow to patient inspiratory flow (GF:IF) is a key factor in the efficiency of trans-nasal aerosol delivery. (2) Methods: In a randomized controlled trial, patients with a history of COPD or asthma and documented positive responses to inhaled bronchodilators in an outpatient pulmonary function laboratory were recruited. Subjects were randomized to receive inhalation at gas flow ratio settings of: GF:IF = 0.5, GF:IF = 1.0, or GF = 50 L/min. Subjects were assigned to inhale saline (control) followed by salbutamol via HFNC with cumulative doses of 0.5 mg, 1.5 mg, 3.5 mg, and 7.5 mg. Spirometry was performed at baseline and 10–12 min after each inhalation. (3) Results: 75 subjects (49 asthma and 26 COPD) demonstrating bronchodilator response were enrolled. Per the robust ATS/ERS criteria no difference was observed between flows, however using the criteria of post-bronchodilator forced expiratory volume in the first second (FEV1) reaching the screening post-bronchodilator FEV1 with salbutamol, a higher percentage of subjects receiving GF:IF = 0.5 met the criteria at a cumulative dose of 1.5 mg than those receiving GF:IF = 1.0, and GF = 50 L/min (64% vs. 29% vs. 27%, respectively, p = 0.011). Similarly at 3.5 mg (88% vs. 54% vs. 46%, respectively, p = 0.005). The effective dose at GF:IF = 0.5 was 1.5 mg while for GF = 50 L/min it was 3.5 mg. (4) Conclusions: During salbutamol delivery via HFNC, cumulative doses of 1.5 mg to 3.5 mg resulted in effective bronchodilation. Applying the robust ATS/ERS criteria no difference was observed between the flows, however using the more sensitive criteria of subjects reaching post screening FEV1 to salbutamol via HFNC, a higher number of subjects responded to the doses of 0.5 mg and 1.5 mg when HFNC gas flow was set at 50% of patient peak inspiratory flow.

Development and Characterization of Excipient Enhanced Growth (EEG) Surfactant Powder Formulations for Treating Neonatal Respiratory Distress Syndrome.

This study aimed to develop and characterize a spray-dried powder aerosol formulation of a commercially available surfactant formulation, Survanta® intratracheal suspension, using the excipient enhanced growth (EEG) approach. Survanta EEG powders were prepared by spray drying of the feed dispersions containing Survanta® (beractant) intratracheal suspension, hygroscopic excipients (mannitol and sodium chloride), and a dispersion enhancer (l-leucine or trileucine) in 5 or 20% v/v ethanol in water using the Buchi Nano Spray Dryer B-90 HP. Powders were characterized for primary particle size, morphology, phospholipid content, moisture content, thermal properties, moisture sorption, and surface activity. The aerosol performance of the powders was assessed using a novel low-volume dry powder inhaler (LV-DPI) device operated with 3-mL volume of dispersion air. At both ethanol concentrations, in comparison to trileucine, l-leucine significantly reduced the primary particle size and span and increased the fraction of submicrometer particles of the Survanta EEG powders. The l-leucine-containing Survanta EEG powders exhibited good aerosolization performance with ≥ 88% of the mass emitted (% nominal) after 3 actuations from the modified LV-DPI device. In addition, l-leucine-containing powders had a low moisture content (< 3% w/w) with transition temperatures close to the commercial surfactant formulation and retained their surface tension reducing activity after formulation processing. A Survanta EEG powder containing l-leucine was developed which showed efficient aerosol delivery from the modified LV-DPI device using a low dispersion air volume.

Review of aerosol delivery in the emergency department.

Aerosol delivery is a vital therapeutic strategy for both adult and pediatric patients presenting to the emergency department with respiratory distress. Aerosolized bronchodilators are frequently used as rescue medications for patients with diagnoses of asthma, chronic obstructive pulmonary disease (COPD), or pneumonia. Historically, emergency department providers utilized jet nebulizers (JNs) for medication delivery, but were challenged by a need for increasingly higher bronchodilator doses to elicit the desired response. Advancements in technology have led to the development of newer specialized aerosol delivery devices and treatment strategies which provide clinicians with improved options for aerosol delivery but may also cause some uncertainty regarding appropriate device selection. Initial investigations comparing these devices presented valuable evidence of in vitro benefit but were unable to demonstrate corresponding improvement in clinical results. More recently there has been an influx of clinical evidence that suggests improved clinical outcomes associated with more efficient aerosol delivery devices such as vibrating mesh nebulizers (VMN) compared to the standard JN device. VMN will likely become an increasingly important tool in emergency department treatment of patients with respiratory distress. Additional controlled studies are needed both to examine the effects of VMN on patient outcomes, as well as to analyze how performance differences between aerosol devices may affect dosing strategies. Future efforts should also focus on applying new evidence in the form of updated consensus guidelines and standardized treatment strategies.

EVALUATION OF AEROSOL DRUG DELIVERY DURING MANUAL RESUSCITATION IN ADULT AND PEDIATRIC PATIENTS

SESSION TITLE: Critical Care Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: The aim of this study was to compare the aerosol delivery from a vibrating mesh nebuliser (VMN) and a jet nebuliser (JN) using a manual resuscitation bag (MRB) in adult and pediatric patients. METHODS: A 2.5ml dose of 1mg/ml of salbutamol (GlaxoSmithKline Ltd., Ireland) was aerosolised as a tracer aerosol with a VMN (Aerogen Solo, Aerogen, Ireland) and a JN (Philips SideStream, Philips, Netherlands). The JN was operated at a standard driving gas flow rate of 7 LPM and run until sputter + 1 minute for each test scenario. The nebulisers were placed distal to an endotracheal tube, (ETT) (adult ID 8.0mm, paediatric ID 5.0mm, Flexicare Medical Ltd, UK). The respiratory circuit was driven by an MRB (Ventlab Airflow 1500ml adult and 550ml paediatric MRB, SunMed LLC, USA) at a rate of 20 BPM and an inspiratory:expiratory ratio (I:E) of 1:2 for both patient cohorts. These breathing rates are on the upper and lower end of the ranges for adult and paediatric patients; however, a BR of 20 BPM and an I:E of 1:2 is considered normal in both patient types [2]. To ensure consistency of dose delivery the same user operated the MRB for each test. A capture filter (Respigard, Baxter, Ireland) was placed between the ETT and a test lung (IMT SmartLung, IMT Analytics, Switzerland). The mass of drug delivered was determined using UV spectrophotometry at 276nm. Results, indicating the dose delivered to the patient, are expressed as the percentage of the nominal dose placed in the nebuliser’s medication cup. A paired t-test analysis was carried out to determine significance of results. Significance was considered at p≤0.05. RESULTS: The use of the VMN resulted in a higher delivered lung dose (%) compared to the JN when used in combination with both the adult (13.19% ± 0.63% VMN versus 3.05% ± 0.33% JN, p = 0.00) and pediatric (3.13% ± 0.34% VMN versus 1.17% ± 0.31% JN, p = 0.034) resuscitation bags. CONCLUSIONS: These findings indicate that the nebuliser type had a significant effect on the efficiency of aerosol delivery to an intubated patient using an MRB, p≤0.05. The VMN delivered significantly more aerosol than the JN in both adult and pediatric patients. CLINICAL IMPLICATIONS: Manual resuscitation plays a pivotal role in airway management and potentially in determining patient outcomes [1]. Medical aerosols can be administered to a patient to stabilize the airways and can be delivered in combination with a manual resuscitation bag. The choice of nebuliser may influence the efficiency of aerosol delivered to the patient.

Nebulized Therapies in COPD: Past, Present, and the Future.

Current guidelines recommend inhalation therapy as the preferred route of drug administration for treating patients with chronic obstructive pulmonary disease (COPD). Inhalation devices consist of nebulizers and handheld inhalers, such as dry-powder inhalers (DPIs), pressurized metered-dose inhalers (pMDIs), and soft mist inhalers (SMIs). Although pMDIs, DPIs and SMIs may be appropriate for most patients with COPD, certain patient populations may have challenges with these devices. Patients who have cognitive, neuromuscular, or ventilatory impairments (and receive limited assistance from caregivers), as well as those with suboptimal peak inspiratory flow may not derive the full benefit from handheld inhalers. A considerable number of patients are not capable of producing a peak inspiratory flow rate to overcome the internal resistance of DPIs. Furthermore, patients may have difficulty coordinating inhalation with device actuation, which is required for pMDIs and SMIs. However, inhalation devices such as spacers and valved holding chambers can be used with pMDIs to increase the efficiency of aerosol delivery. Nebulized treatment provides patients with COPD an alternative administration route that avoids the need for inspiratory flow, manual dexterity, or complex hand-breath coordination. The recent approval of two nebulized long-acting muscarinic antagonists has added to the extensive range of nebulized therapies in COPD. Furthermore, with the availability of quieter and more portable nebulizer devices, nebulization may be a useful treatment option in the management of certain patient populations with COPD. The aim of this narrative review was to highlight recent updates and the treatment landscape in nebulized therapy and COPD. We first discuss the pathophysiology of patients with COPD and inhalation device considerations. Second, we review the updates on recently approved and newly marketed nebulized treatments, nebulized treatments currently in development, and technological advances in nebulizer devices. Finally, we discuss the current applications of nebulized therapy in patients with COPD.

In Vitro Evaluation of Aerosol Performance and Delivery Efficiency During Mechanical Ventilation Between Soft Mist Inhaler and Pressurized Metered-Dose Inhaler

Soft mist inhalers (SMIs) generate aerosols with a smaller particle size than pressurized metered-dose inhalers (pMDIs). However, the whole-span particle size distribution (PSD) of SMIs and the optimal delivery method of SMIs during mechanical ventilation have not been fully investigated. This study aimed to measure the PSD of the SMI alone and the SMI coupled to an inhalation aid (eg, a spacer, a valved holding chamber), as well as the delivery efficiency of SMI in different actuation timings and circuit positions during mechanical ventilation. As a suitable comparison, the pMDI was chosen for the same measurement. SMIs (2.5 μg/actuation of tiotropium) were compared with pMDIs (100 μg/actuation of salbutamol). A microorifice uniform deposit impactor was utilized for the particle sizing of drug aerosols generated by inhalers alone, inhalers with a spacer, and inhalers with a valved holding chamber. To optimize the delivery efficiency of both inhalers during mechanical ventilation, the operating parameters included the circuit positions and actuation timings in the ventilator circuit. Particle sizes and inhaled doses were measured with an optical particle sizer and filters used to collect and quantify the drug, respectively. The SMI generated a smaller mass medium aerodynamic diameter (MMAD) than that from the pMDI. The extrafine-particle fraction (EFPF, < 1 μm) of the SMI was significantly higher than that of the pMDI. With the use of either inhalation aid, the MMAD of both inhalers decreased, and both inhalers with inhalation aid showed significant increases in EFPF. During mechanical ventilation, the optimum way to deliver the SMI and pMDI was at 15 cm from the Y-piece and actuated at the end of expiration and the onset of inspiration, respectively. The SMI with an inhalation aid showed marginal improvement on the PSD. The inhaler type, actuation timing, and position within the circuit also played important roles in delivery efficiency during mechanical ventilation.

The Clinical Impact of Flow Titration on Epoprostenol Delivery via High Flow Nasal Cannula for ICU Patients with Pulmonary Hypertension or Right Ventricular Dysfunction: A Retrospective Cohort Comparison Study.

(1) Background: inhaled epoprostenol (iEPO) delivered via high-flow nasal cannula (HFNC) has been reported to be effective for pulmonary hypertension and right ventricular dysfunction. In vitro studies have identified HFNC gas flow as a key factor in trans-nasal aerosol delivery efficiency; however, little evidence is available on the clinical impact of flow titration on trans-nasal aerosol delivery. At our institution, iEPO via HFNC was initiated in 2015 and the concept of flow titration during iEPO via HFNC has been gradually accepted and carried out by clinicians in the recent years. (2) Methods: a retrospective review of the electronic medical records for all adult patients who received iEPO via HFNC in a tertiary teaching hospital. Pre- and post- iEPO responses were reported for patients whose HFNC flow was titrated or maintained constant during iEPO delivery. Positive response to iEPO was defined as the reduction of mean pulmonary arterial pressure (mPAP) > 10% for pulmonary hypertension patients or the improvement of oxygenation [pulse oximetry (SpO2)/fraction of inhaled oxygen (FIO2)] > 20%. The number of responders to iEPO was compared between groups with titrated vs constant flow. (3) Results: 51 patients who used iEPO to treat pulmonary hypertension and/or right ventricular dysfunction were reviewed. Following iEPO administration via HFNC, mPAP decreased (43.6 ± 11.7 vs. 36.3 ± 9.7 mmHg, p < 0.001). Among the 51 patients, 24 had concomitant refractory hypoxemia, their oxygenation (SpO2/FIO2) improved after iEPO delivery (127.8 ± 45.7 vs. 157.6 ± 62.2, p < 0.001). During iEPO initiation, gas flow was titrated in 25 patients and the remaining 26 patients used constant flow. The percentage of patients in the flow titration group who met the criteria for a positive response was higher compared to the group with constant flow (85.7% vs. 50%, p = 0.035). Pre- vs post-iEPO responses were significant in the flow titration group included improvement in cardiac output (p = 0.050), cardiac index (p = 0.021) and FIO2 reduction (p = 0.016). These improvements in hemodynamics and FIO2 were not observed in the constant flow group. (4) Conclusion: in patients with pulmonary hypertension and/or right ventricular dysfunction, trans-nasal iEPO decreased pulmonary arterial pressure. It also improved oxygenation in patients with combined refractory hypoxemia. These improvements were more evident in patients whose gas flow was titrated during iEPO initiation than those patients using constant flow.

Devices for Improved Delivery of Nebulized Pharmaceutical Aerosols to the Lungs

Nebulizers have a number of advantages for the delivery of inhaled pharmaceutical aerosols, including the use of aqueous formulations and the ability to deliver process-sensitive proteins, peptides, and biological medications. A frequent disadvantage of nebulized aerosols is poor lung delivery efficiency, which wastes valuable medications, increases delivery times, and may increase side effects of the medication. A focus of previous development efforts and previous nebulizer reviews, has been an improvement of the underlying nebulization technology controlling the breakup of a liquid into droplets. However, for a given nebulization technology, a wide range of secondary devices and strategies can be implemented to significantly improve lung delivery efficiency of the aerosol. This review focuses on secondary devices and technologies that can be implemented to improve the lung delivery efficiency of nebulized aerosols and potentially target the region of drug delivery within the lungs. These secondary devices may (1) modify the aerosol size distribution, (2) synchronize aerosol delivery with inhalation, (3) reduce system depositional losses at connection points, (4) improve the patient interface, or (5) guide patient inhalation. The development of these devices and technologies is also discussed, which often includes the use of computational fluid dynamic simulations, three-dimensional printing and rapid prototype device and airway model construction, realistic in vitro experiments, and in vivo analysis. Of the devices reviewed, the implementation of streamlined components may be the most direct and lowest cost approach to enhance aerosol delivery efficiency within nonambulatory nebulizer systems. For applications involving high-dose medications or precise dose administration, the inclusion of active devices to control aerosol size, guide inhalation, and synchronize delivery with inhalation hold considerable promise.

Albuterol Delivery Efficiency in a Pediatric Model of Noninvasive Ventilation With a Single-Limb Circuit.

Pediatric patients treated with noninvasive ventilation (NIV) are frequently given aerosol therapy. Limited pediatric data are available on the efficiency of aerosol delivery efficiency. We evaluated the effect of different nebulizers, positions in the single-limb ventilator circuit, and ventilator settings on the efficiency of aerosol delivery in a model of pediatric NIV. We hypothesized that using a vibrating mesh nebulizer, placing the nebulizer after the circuit leak, and not using the highest inspiratory positive airway pressure would increase aerosol delivery efficiency. We connected a breathing simulator in series to a low-dead-space filter holder (lung dose) and to an anatomically correct face/airway model of a 5-y-old child. A mask with an entrainment elbow was connected to a ventilator operated in a NIV bi-level mode and assembled with a single-limb heated-wired circuit. Inspiratory/expiratory pressures of either 15/5 or 20/5 cm H2O were used. We studied 3 different jet nebulizers and 2 vibrating mesh nebulizers loaded with albuterol solution (2.5 mg/3 mL). Albuterol was measured with spectrophotometry. The outcome measure was the efficiency of aerosol delivery (ie, lung dose expressed as percentage of the nominal dose). Vibrating mesh nebulizers placed after the exhalation port of the circuit had the highest delivery efficiency, even compared with a vibrating mesh nebulizer integrated into the mask. Placing the nebulizer after the exhalation port of the circuit increased efficiency for all nebulizers. Vibrating mesh nebulizers were more efficient than jet nebulizers, regardless of their position in the circuit. Increasing the inspiratory pressure resulted in a variable effect on aerosol-delivery efficiency. In a model of pediatric NIV using a single-limb circuit, aerosol delivery devices were more efficient when placed after the exhalation port of the ventilator circuit. Vibrating mesh nebulizers were more efficient than jet nebulizers.

Polydisperse Microparticle Transport and Deposition to the Terminal Bronchioles in a Heterogeneous Vasculature Tree

The atmospheric particles from different sources, and the therapeutic particles from various drug delivery devices, exhibit a complex size distribution, and the particles are mostly polydisperse. The limited available in vitro, and the wide range of in silico models have improved understanding of the relationship between monodisperse particle deposition and therapeutic aerosol transport. However, comprehensive polydisperse transport and deposition (TD) data for the terminal airways is still unavailable. Therefore, to benefit future drug therapeutics, the present numerical model illustrates detailed polydisperse particle TD in the terminal bronchioles for the first time. Euler-Lagrange approach and Rosin-Rammler diameter distribution is used for polydisperse particles. The numerical results show higher deposition efficiency (DE) in the right lung. Specifically, the larger the particle diameter (dp > 5 μm), the higher the DE at the bifurcation area of the upper airways is, whereas for the smaller particle (dp < 5 μm), the DE is higher at the bifurcation wall. The overall deposition pattern shows a different deposition hot spot for different diameter particle. These comprehensive lobe-specific polydisperse particle deposition studies will increase understanding of actual inhalation for particle TD, which could potentially increase the efficiency of pharmaceutical aerosol delivery at the targeted position of the terminal airways.

Efficient Nose-to-Lung Aerosol Delivery with an Inline DPI Requiring Low Actuation Air Volume.

To demonstrate efficient aerosol delivery through an in vitro nasal model using a dry powder inhaler (DPI) requiring low actuation air volumes (LV) applied during low-flow nasal cannula (LFNC) therapy. A previously developed LV-DPI was connected to a LFNC system with 4mm diameter tubing. System connections and the nasal cannula interface were replaced with streamlined components. To simulate nasal respiration, an in vitro nasal model was connected to a downstream lung simulator that produced either passive or deep nasal respiration. Performance of a commercial mesh nebulizer system was also considered. For the optimized system, steady state cannula emitted dose was 75% of the capsule loaded dose. With cyclic nasal breathing, delivery efficiency to the tracheal filter was 53-55% of the loaded dose, which was just under the design target of 60%. Compared with a commercially available mesh nebulizer, the optimal LV-DPI was 40-fold more efficient and 150 times faster in terms of delivering aerosol to the lungs. The optimized LV-DPI system is capable of high efficiency lung delivery of powder aerosols through a challenging nasal cannula interface.