Comparison of airway pressures and expired gas washout for nasal high flow versus CPAP in child airway replicas.

BACKGROUND: For children and adults, the standard treatment for obstructive sleep apnea is the delivery of continuous positive airway pressure (CPAP). Though effective, CPAP masks can be uncomfortable to patients, contributing to adherence concerns. Recently, nasal high flow (NHF) therapy has been investigated as an alternative, especially in CPAP-intolerant children. The present study aimed to compare and contrast the positive airway pressures and expired gas washout generated by NHF versus CPAP in child nasal airway replicas. METHODS: NHF therapy was investigated at a flow rate of 20 L/min and compared to CPAP at 5 cmH2O and 10 cmH2O for 10 nasal airway replicas, built from computed tomography scans of children aged 4-8 years. NHF was delivered with three different high flow nasal cannula models provided by the same manufacturer, and CPAP was delivered with a sealed nasal mask. Tidal breathing through each replica was imposed using a lung simulator, and airway pressure at the trachea was recorded over time. For expired gas washout measurements, carbon dioxide was injected at the lung simulator, and end-tidal carbon dioxide (EtCO2) was measured at the trachea. Changes in EtCO2 compared to baseline values (no intervention) were assessed. RESULTS: NHF therapy generated an average positive end-expiratory pressure (PEEP) of 5.17 ± 2.09 cmH2O (mean ± SD, n = 10), similar to PEEP of 4.95 ± 0.03 cmH2O generated by nominally 5 cmH2O CPAP. Variation in tracheal pressure was higher between airway replicas for NHF compared to CPAP. EtCO2 decreased from baseline during administration of NHF, whereas it increased during CPAP. No statistical difference in tracheal pressure nor EtCO2 was found between the three high flow nasal cannulas. CONCLUSION: In child airway replicas, NHF at 20 L/min generated average PEEP similar to CPAP at 5 cm H2O. Variation in tracheal pressure was higher between airway replicas for NHF than for CPAP. The delivery of NHF yielded expired gas washout, whereas CPAP impeded expired gas washout due to the increased dead space of the sealed mask.

The influence of flowrate and gas density on positive airway pressure for high flow nasal cannula applied to infant airway replicas.

High flow nasal cannula (HFNC) therapy has been previously shown to produce positive upper airway pressures in adult and child patients. This work aimed to evaluate and quantify the effects of HFNC flowrate and gas type on airway pressures measured in vitro in infant airway replicas. Ten realistic infant airway replicas, extending from nares to trachea, were connected in turn to a lung simulator and were supplied gas flows through HFNC. Air and heliox were each provided at two weight-indexed flowrates, 1 l/min/kg and 2 l/min/kg. Pressure and lung volume were continuously measured during simulated breathing. For constant simulated patient effort, no statistically significant change in tidal volume was measured between baseline and lower or higher HFNC flowrates, nor was there any significant difference in tidal volume between air and heliox. Tracheal pressure increased with increasing HFNC flow rate, and was highly variable between airway replicas. Higher pressures were measured for air versus heliox. For air supplied at 2 l/min/kg, average airway pressures in excess of 4 cm H2O were generated, with positive end-expiratory pressure (PEEP) ranging from 2.5 to nearly 12 cm H2O across the replicas. A predictive correlation for PEEP was proposed based on supplied gas density and flow velocities exiting the cannula and nares, and was able to account for a portion of variability between airway replicas (R2 = 0.913). Additionally, PEEP was well correlated with, and predictive of, expiratory peak pressure (R2 = 0.939) and average inspiratory pressure (R2 = 0.944).

Correlation of high flow nasal cannula outlet area with gas clearance and pressure in adult upper airway replicas.

BACKGROUND: Primary benefits of high flow nasal cannula therapy include washout of carbon dioxide rich exhaled gas and increased airway pressures during tidal breathing. This work reports on the influence of high flow nasal cannula outlet area on upper airways gas clearance and tracheal pressures using measurements in five realistic adult nose-throat airway replicas. METHODS: Two commercial high flow nasal cannulas and one generic nasal cannula of varying size were compared. 100% oxygen was supplied via cannulas at flow rates ranging from 30 to 90l/min to replicas originally filled with air, and oxygen concentrations at the larynx and trachea were compared over time. Additionally, and separately, replicas were connected to a mechanical lung simulator to simulate tidal breathing while undergoing high flow nasal cannula therapy, with tracheal pressure-time waveforms recorded. FINDINGS: Faster gas clearance corresponded with higher flow rates (P<0.001), and with smaller cannula outlet area (P<0.001). Observed pressures were in approximate agreement with limited available in-vivo data in the literature. Between 0 and 60L/min cannula flow rates, tracheal positive end expiratory pressures increase was greater with the smallest cannula (∆PPEEP=785SD(185) Pa) compared to the largest cannula (∆PPEEP=380SD(120)Pa). Regression analysis indicates that positive end expiratory pressure is proportional to the square of flow velocities exiting the cannula and nares (R2=0.906). INTERPRETATION: Since increased pressure and clearance rate have been associated with improved clinical outcomes in previous studies, our results suggest that smaller cannula outlet area may be preferable.

Theoretical and experimental evaluation of the effects of an argon gas mixture on the pressure drop through adult tracheobronchial airway replicas.

Argon has the potential to be a novel inhaled therapeutic agent, owing to the neuroprotective and organoprotective properties demonstrated in preclinical studies. Before human trials are performed, an understanding of varying gas properties on airway resistance during inhalation is essential. This study predicts the effect of an 80% argon/20% oxygen gas mixture on the pressure drop through conducting airways, and by extension the airway resistance, and then verifies these predictions experimentally using 3-D printed adult tracheobronchial airway replicas. The predicted pressure drop was calculated using established analytical models of airway resistance, incorporating the change in viscosity and density of the 80% argon/20% oxygen mixture versus that of air. Predicted pressure drop for the argon mixture increased by approximately 29% compared to that for air. The experimental results were consistent with this prediction for inspiratory flows ranging from 15 to 90slpm. These results indicate that established analytical models may be used to predict increases in conducting airway resistance for argon/oxygen mixtures, compared with air. Such predictions are valuable in predicting average patient response to breathing argon/oxygen mixtures, and in selecting or designing delivery systems for use in administration of argon/oxygen mixtures to critically ill or injured patients.

Comparison of in vitro deposition of pharmaceutical aerosols in an idealized child throat with in vivo deposition in the upper respiratory tract of children.

PURPOSE: Deposition of drug emitted from two commercially available inhalers was measured in an in vitro child oral airway model and compared to existing in vivo data to examine the ability of the child model to replicate in vivo deposition. METHODS: In vitro deposition of drug from a QVAR® pressurized metered dose inhaler (pMDI) and Pulmicort® Turbuhaler® dry powder inhaler (DPI) in an Idealized Child Throat (1) and downstream filter was measured using UV spectroscopy and simulated realistic breathing profiles. Potential effects of ambient relative humidity ranging from 10% to 90% on deposition were also considered. RESULTS: In vitro QVAR pMDI deposition in the idealized mouth-throat at 50% RH (39.2 ± 2.3% of delivered dose) compared well (p>0.05) with in vivo extrathoracic deposition in asthmatic children age 8 to 14 (45.8 ± 12.3%). In vitro Turbuhaler DPI deposition in the idealized mouth-throat at 50% RH (69.0 ± 1.5%) matched in vivo extrathoracic deposition (p>0.05) in 6 to 16 year old children with cystic fibrosis (70.4 ± 21.2%). The effects of ambient humidity were found to be insignificant for Turbuhaler and minor for QVAR. CONCLUSIONS: The Idealized Child Throat successfully mimics in vivo deposition data in school age children for the inhalers tested, and may provide a standard platform for optimizing pediatric treatment with inhaled pharmaceutical aerosols.

Distribution of effervescent inhalable nanoparticles after pulmonary delivery: an in vivo study.

BACKGROUND: Effervescent inhalable nanoparticles (NPs) have previously been shown to be a promising alternative to conventional lung cancer treatment in animals. This study investigates the biodistribution of effervescent inhalable NPs after a single dose administration via pulmonary route in lung cancer-bearing mice. METHODS & RESULTS: Whole-body autoradiography and confocal laser-scanning microscopy (CLSM) were used to investigate the distribution of inhalable NPs loaded in an effervescent microcarrier. Inhalable doxorubicin-loaded NPs were tagged with 14C for whole-body autoradiography, or with fluorescein isothiocyanate for CLSM imaging. After pulmonary delivery, NPs were widely disseminated in the lungs with a long retention time (24 h). The heart was radioactivity free at all time points of the study. CLSM images showed that inhalable NPs were taken up by cells and that doxorubicin was released to the cell nuclei. CONCLUSION: This is the first study to investigate the distribution of inhalable NPs in a lung cancer-bearing animal model. Inhalable NPs achieved deep lung deposition, were actively released from microcarrier particles, spread to different parts of the lung and released doxorubicin in vivo. These NP characteristics contribute to the efficacy of effervescent inhalable NPs as a lung cancer treatment.

Inhalable nanoparticles, a non-invasive approach to treat lung cancer in a mouse model.

Doxorubicin-loaded nanoparticles (NPs) were incorporated into inhalable effervescent and non-effervescent carrier particles using a spray-freeze drying technique. The prepared inhalable powders were tested in a tumor bearing Balb/c mouse model. Control mice were treated with blank inhalable NPs, inhalable lactose powder containing free doxorubicin, and intravenous injections of a suspension of doxorubicin NPs, doxorubicin solution, or saline solution. The survival of treatment groups was plotted with Kaplan-Meier curves. Animals treated with inhalable effervescent nanoparticle powder containing 30µg doxorubicin showed a highly significant improvement in survival compared to all other treatment groups. Mice in control groups treated with doxorubicin solution or doxorubicin NPs as intravenous injection, died in less than 50 days. Inhalable free doxorubicin showed high cardiac toxicity. Pathological samples showed large tumor masses in the lungs of animals not treated or treated with i.v. injections of doxorubicin NPs or doxorubicin solution. The lungs of animals treated with inhalable effervescent doxorubicin NPs showed fewer and much smaller tumors compared to the control groups, as visualized by MRI imaging which confirmed the observed pathology results. The present study demonstrates that inhalable effervescent doxorubicin NPs are an effective way to treat lung cancer. This non-invasive route of administration might change the way lung cancer is treated in the future.

Toward modern inhalational bacteriophage therapy: nebulization of bacteriophages of Burkholderia cepacia complex.

Antibiotic-resistant bacterial infections have renewed interest in finding substitute methods of treatment. The purpose of the present in vitro study was to investigate the possibility of respiratory delivery of a Burkholderia cepacia complex (BCC) bacteriophage by nebulized aerosol administration. Bacteriophages in isotonic saline were aerosolized with Pari LC star and eFlow nebulizers, at titers with mean value (standard deviation) of 2.15 x 10(8) (1.63 x 10(8)) plaque-forming unit (PFU)/mL in 2.5-mL nebulizer fills. The breathing pattern of an adult was simulated using a pulmonary waveform generator. During breath simulation, the size distributions of the nebulized aerosol were measured using phase doppler anemometry (PDA). Efficiency of nebulizer delivery was subsequently determined by collection of aerosol on low resistance filters and measurement of bacteriophage titers. These filter titers were used as input data to a mathematical lung deposition model to predict regional deposition of bacteriophages in the lung and initial bacteriophage titers in the liquid surface layer of each conducting airway generation. The results suggest that BCC bacteriophages can be nebulized successfully within a reasonable delivery time and predicted titers in the lung indicate that this method may hold potential for treatment of bacterial lung infections common among cystic fibrosis patients.

MRI measurement of regional lung deposition in mice exposed nose-only to nebulized superparamagnetic iron oxide nanoparticles.

Superparamagnetic iron oxide nanoparticles show potential in magnetic targeting of inhaled aerosols to localized sites within the lung. These particles are also used as contrast agents in magnetic resonance imaging (MRI). In the present work, we examine the feasibility of measuring regional lung deposition of iron oxide nanoparticles using MRI. Mice were exposed nose-only to nebulized superparamagnetic iron oxide nanoparticles. The droplet size distribution in the inhalation chamber was measured using a time-of-flight device. Regional concentrations of iron in the left and right lung were assessed with MRI by measuring the longitudinal relaxation times (T(1)) of the lung tissue in exposed mice, compared to a baseline group. Regional concentrations of iron in the lungs of the mice ranged from 1.1 +/- 0.8 microg/cm(3) (mean +/- one standard deviation, n = 6) in peripheral lung regions to 2.7 +/- 1.4 microg/cm(3) in the central lung, with no significant difference between the left and right lung. The nebulized droplets in the inhalation chamber had mass median aerodynamic diameter (MMAD) of 5.6 +/- 0.8 microm, with a geometric standard deviation (GSD) of 1.30 +/- 0.03 (both values expressed as mean +/- one standard deviation, n = 6). MRI shows promise for in vivo measurement of regional lung concentrations of superparamagnetic iron oxide nanoparticles, and may be useful in studies of lung deposition and clearance.

Optimization of a two-step desolvation method for preparing gelatin nanoparticles and cell uptake studies in 143B osteosarcoma cancer cells.

PURPOSE: To establish a matrix of parameters to synthesize nanoparticles of different sizes and to investigate the cellular uptake of these nanoparticles by osteosarcoma cancer cells in order to investigate their potential as therapeutic drugdelivery carriers. METHODS: Gelatin A and B were used to synthesize nanoparticles by a two-step desolvation process. Different parameters were investigated, including temperature, pH, concentration of glutaraldehyde, type of desolvating agent and nature of gelatin. For cell uptake studies, Texas Red labeled nanoparticles were incubated with 143B osteosarcoma cells and then evaluated using confocal laser scanning microscopy (CLSM). RESULTS: The systematic investigation of the synthesis parameters showed that it is possible to prepare gelatin-based nanoparticles with different particle sizes and a narrow size distribution. Temperature and nature of the gelatin were the most important synthesis factors. Bioimaging using CLSM showed uptake of the nanoparticles by 143B osteosarcoma cancer cells. CONCLUSIONS: Osteosarcoma cancer cells take up gelatin nanoparticles. This might improve the clinical effectiveness of anti-cancer treatments if nanoparticles are used as a drug delivery system and has important implications for future cancer treatment strategies.

Formulation and cytotoxicity of doxorubicin nanoparticles carried by dry powder aerosol particles.

Regional drug delivery via dry powder inhalers offers many advantages in the management of pharmaceutical compounds for the prevention and treatment of respiratory diseases. In the present study, doxorubicin (DOX)-loaded nanoparticles were incorporated as colloidal drug delivery system into inhalable carrier particles using a spray-freeze-drying technique. The cytotoxic effects of free DOX, carrier particles containing blank nanoparticles or DOX-loaded nanoparticles on H460 and A549 lung cancer cells were assessed using a colorimetric XTT cell viability assay. The mean geometric carrier particle size of 10+/-4 microm was determined using confocal laser scanning microscopy. DOX-loaded nanoparticles had a particle size of 173+/-43 nm after re-dissolving of the carrier particles. Compared to H460 cells, A549 cells showed less sensitivity to the treatment with free DOX. The DOX-nanoparticles showed in both cell lines a higher cytotoxicity at the highest tested concentration compared to the blank nanoparticles and the free DOX. The cell uptake of free DOX and DOX delivered by nanoparticles was confirmed using confocal laser scanning microscopy. This study supports the approach of lung cancer treatment using nanoparticles in dry powder aerosol form.

Spray-freeze-dried liposomal ciprofloxacin powder for inhaled aerosol drug delivery.

Spray-freeze drying was utilized to manufacture a liposomal powder formulation containing ciprofloxacin as a model active component. The powder forms liposomally encapsulated ciprofloxacin when wetted. Aerosol properties of this formulation were assessed using a new passive inhaler, in which the powder was entrained at a flow rate of 60l/min. A mass median aerodynamic diameter (MMAD) of 2.8 microm was achieved for this formulation. Using the experimental dispersion testing data, ciprofloxacin concentration in the airway surface liquid (ASL) was calculated using a Lagrangian deposition model. The reconstitution of the powder in various aqueous media gave drug encapsulation efficiencies as follows: 50% in water, 93.5% in isotonic saline, 80% in bovine mucin, 75% in porcine mucus and 73% in five-fold-diluted ex vivo human cystic fibrosis patient sputum.