Inhaled Mass Research Articles

Multidrug Aerosol Delivery During Mechanical Ventilation.

Background: In the critically ill, pulmonary vasodilators are often provided off label to intubated patients using continuous nebulization. If additional aerosol therapies such as bronchodilators or antibiotics are needed, vasodilator therapy may be interrupted. This study assesses aerosol systems designed for simultaneous delivery of two aerosols using continuous nebulization and bolus injection without interruption or circuit disconnection. Methods: One i-AIRE dual-port breath-enhanced jet nebulizer (BEJN) or two Aerogen® Solo vibrating mesh nebulizers (VMNs) were installed on the dry side of the humidifier. VMN were stacked; one for infusion and the second for bolus drug delivery. The BEJN was powered by air at 3.5 L/min, 50 psig. Radiolabeled saline was infused at 5 and 10 mL/h with radiolabeled 3 and 6 mL bolus injections at 30 and 120 minutes, respectively. Two adult breathing patterns (duty cycle 0.13 and 0.34) were tested with an infusion time of 4 hours. Inhaled mass (IM) expressed as % of initial syringe activity (IM%/min) was monitored in real time with a ratemeter. All delivered radioaerosol was collected on a filter at the airway opening. Transients in aerosol delivery were measured by calibrated ratemeter. Results: IM%/h during continuous infusion was linear and predictable, mean ± standard deviation (SD): 2.12 ± 1.45%/h, 2.47 ± 0.863%/h for BEJN and VMN, respectively. BEJN functioned without incident. VMN continuous aerosol delivery stopped spontaneously in 3 of 8 runs (38%); bolus delivery stopped spontaneously in 3 of 16 runs (19%). Tapping restarted VMN function during continuous and bolus delivery runs. Bolus delivery IM% (mean ± SD): 20.90% ± 7.01%, 30.40% ± 11.10% for BEJN and VMN, respectively. Conclusion: Simultaneous continuous and bolus nebulization without circuit disconnection is possible for both jet and mesh technology. Monitoring of VMN devices may be necessary in case of spontaneous interruption of nebulization.

Real-Time Analysis of Dry-Side Nebulization With Heated Wire Humidification During Mechanical Ventilation.

Recent observational studies of nebulizers placed on the wet side of the humidifier suggest that, after some time, considerable condensation can form, which triggers an occlusion alarm. In the current study, an inline breath-enhanced jet nebulizer was tested and compared in vitro with a vibrating mesh nebulizer on the humidifier dry-inlet side of the ventilator circuit. Two duty cycle breathing patterns were tested during continuous infusion (5 or 10 mL/h) with and without dynamic changes in infusion flow and duty cycle, or bolus delivery (3 or 6 mL) of radiolabeled saline solution. Inhaled mass (IM) was measured by a real-time ratemeter (µCi/min) and analyzed by multiple linear regression. During simple continuous infusion, IM increased linearly for both nebulizer types. IM variability was attributable to the duty cycle (P < .001) (34%) and infusion flow (P < .001) (32%) but independent of nebulizer technology (P = .38) (7%). Dynamic continuous infusion studies that simulate clinical scenarios with ventilator and pump flow changes demonstrated a linear increase in the rate of aerosol that was dependent on pump flow (P < .001) (63%) and minimally dependent on the duty cycle (P = .003) (8%). During bolus treatments, IM increased linearly to plateau. IM variability was attributable to the duty cycle (P < .001) (40%) and residual radioactivity in the nebulizer (P < .001) (20%). Separate analysis revealed that the vibrating mesh nebulizer residual volume contributed 16% of the variability and inline breath-enhanced jet nebulizer contributed 5%. IM variability was independent of bolus volume (P = .82) (1%). System losses were similar (the inline breath-enhanced jet nebulizer: 32% residual in nebulizer; the vibrating mesh nebulizer: 34% in circuitry). Aerosol delivery during continuous infusion and bolus delivery was comparable between the inline breath-enhanced jet nebulizer and the vibrating mesh nebulizer, and was determined by pump flow and initial ventilator settings. Further adjustments in ventilator settings did not significantly affect drug delivery. Expiratory losses predicted by the duty cycle were reduced with placement of the nebulizer near the ventilator outlet.

Real-Time In Vitro Assessment of Aerosol Delivery During Mechanical Ventilation.

Background: A new real-time method for assessing factors determining aerosol delivery is described.Methods: A breath-enhanced jet nebulizer operated in a ventilator/heated humidifier system was tested during bolus and continuous infusion aerosol delivery. 99mTc (technetium)/saline was either injected (3 or 6 mL) or infused over time into the nebulizer. A shielded gamma ratemeter was oriented to count radioaerosol accumulating on an inhaled mass (IM) filter at the airway opening of a test lung. Radioactivity measured at 2–10-minute intervals was expressed as % nebulizer charge (bolus) or % syringe activity per minute infused. All circuit parts were measured and imaged by gamma camera to determine mass balance.Results: Ratemeter activity quantitatively reflected immediate changes in IM: 3 and 6 mL bolus IM% = 16.1 and 18.8% in 6 and 14 minutes, respectively; infusion IM% = 0.64 + 0.13 (run time, min), R2 0.999. Effect of nebulizer priming and system anomalies were readily detected in real time. Mass balance (basis = dose infused in 90 minutes): IM 39.2%, breath-enhanced jet nebulizer residual 35.5%, circuit parts including humidifier 23.4%, and total recovery 98.1%. Visual analysis of circuit component images identified sites of increased deposition.Conclusion: Real-time ratemeter measurement with gamma camera imaging provides operational feedback during in vitro testing procedures and yields a detailed analysis of the parameters influencing drug delivery during mechanical ventilation. This method of analysis facilitates assessment of device function and influence of circuit parameters on drug delivery.

Factors Determining Continuous Infusion Aerosol Delivery During Mechanical Ventilation.

Continuous nebulization of prostacyclins and albuterol by infusion pump during mechanical ventilation evolved as a popular off-label treatment for severe hypoxemic respiratory failure and asthma. Most institutions use a vibrating mesh nebulizer. A new breath-enhanced jet nebulizer is a potential alternative. This study was designed to compare these devices to better define factors influencing continuous infusion aerosol delivery. Device function, ventilator settings, and infusion pump flow were studied invitro. Using a bench model of adult mechanical ventilation, radiolabeled saline was infused at6 flows (1.5-12mL/h) into test nebulizers; 4 examples of each were used in rotation to test device reproducibility. Four breathing patterns with duty cycles (percentage of inspiratory time) ranging from0.13 to0.34 were tested. The vibrating mesh nebulizer was installed on the "dry" side of the heated humidifier (37°C). The breath-enhanced jet nebulizer, installed on the "wet" side, was powered by air at3.5L/min and50psi. Infusion time was1h. Inhaled mass of aerosol was collected on a filter at the airway opening. Inhaled mass was expressed as the percentage of the initial syringe radioactivity delivered per hour. Radioactivity deposited in the circuit was measured with a gamma camera. Data were analyzed with multiple linear regression. Variation in inhaled mass was significantly explained by pump flow and duty cycle (R20.92) and not by nebulizer technology. Duty cycle effects were more apparent at higher pump flow. Vibrating mesh nebulizers failed to nebulize completely in 20% of the test runs. Mass balance indicated that vibrating mesh nebulizers deposited 15.3% in the humidifier versus 0.2% for breath-enhanced jet nebulizer. Aerosol delivery was determined by infusion pump flow and ventilator settings with comparable aerosol delivery between devices. The breath-enhanced jet nebulizer was more reliable than the vibrating mesh nebulizer;10-12mL/h was the maximum infusion flow for both nebulizer technologies.

Characterisation of 40 mg/ml and 100 mg/ml tobramycin formulations for aerosol therapy with adult mechanical ventilation

BackgroundPreservative-free tobramycin is commonly used as aerosolized therapy for ventilator associated pneumonia. The comparative delivery profile of the formulations of two different concentrations (100 mg/ml and 40 mg/ml) is unknown. This study aims to evaluate the aerosol characteristics of these tobramycin formulations in a simulated adult mechanical ventilation model. MethodsSimulated adult mechanical ventilation set up and optimal settings were used in the study. Inhaled mass study was performed using bacterial/viral filters at the tip of the tracheal tube and in the expiratory limb of circuit. Laser diffractometer was used for characterising particle size distribution. The physicochemical characteristics of the formulations were described and nebulization characteristics compared using two airways, an endotracheal tube (ET) and a tracheostomy tube (TT). For each type of tube, three internal tube diameters were studied, 7 mm, 8 mm and 9 mm. ResultsThe lung dose was significantly higher for 100 mg/ml solution (mean 121.3 mg vs 41.3 mg). Viscosity was different (2.11cp vs 1.58cp) for 100 mg/ml vs 40 mg/ml respectively but surface tension was similar. For tobramycin 100 mg/ml vs 40 mg/ml, the volume median diameter (2.02 vs 1.9 μm) was comparable. The fine particle fraction (98.5 vs 85.4%) was higher and geometric standard deviation (1.36 vs 1.62 μm) was significantly lower for 100 mg/ml concentration. Nebulization duration was longer for 100 mg/ml solution (16.9 vs 10.1 min). The inhaled dose percent was similar (30%) but the exhaled dose was higher for 100 mg/ml solution (18.9 vs 10.4%). The differences in results were non-significant for type of tube or size except for a small but statistically significant reduction in inhaled mass with TT compared to ET (0.06%). ConclusionAerosolized tobramycin 100 mg/ml solution delivered higher lung dose compared to tobramycin 40 mg/ml solution. Tracheal tube type or size did not influence the aerosol characteristics and delivery parameters.

Longitudinal Evaluation of Compressor/Nebulizer Performance

Inhaled medications are the mainstay of treatment for maintenance of lung health in patients with cystic fibrosis (CF). Compressor/nebulizer units are used an average of 100-120 min/d by patients with CF. Each compressor/nebulizer has unique flow/pressure characteristics that affect particle size distribution and drug output rate. Few data are available regarding longitudinal performance of compressor/nebulizers. We hypothesized that their use over a 24-wk period under conditions similar to those of patients with CF would affect their performance. Four new units of compressor/reusable nebulizers from 3 brands (Pari Vios/Pari LC Plus, Pulmo-Aide 5650D/Viox, and Inspiration Elite/SideStream Plus) commonly used by patients with CF were tested. Compressor/nebulizers were operated for 1 h twice daily 5 d/wk for 24 wk. Compressor flow/pressure characteristics were measured every 6 wk. Maximal flow was recorded without and with the nebulizer (MF and MF/NEB, respectively). Pressure was recorded at zero flow (MP) and at MF/NEB (P/NEB). Particle size distribution, inhaled mass (IM), and IM in respirable range were evaluated at baseline and every 12 wk. Vios had statistically significant declines in MP and P/NEB at each measurement compared with baseline (45.8 and 32.6 psi for MP and 16.7 and 14.3 psi for P/NEB at wk 0 and 24, respectively, P < .05), but other compressors did not. MF and MF/NEB were stable over time but significantly varied among brands. Vios had the greatest slope of flow/pressure relationship (Vios > Pulmo-Aide > Inspiration Elite). Two Vios units stopped working at wk 11 and 24, respectively. All compressors maintained baseline IM, IM in respirable range, and aerosol characteristics. Long-term use of compressor/nebulizers in a regimen similar to that of patients with CF affected their performance. Pari Vios was the most affected brand, with declines in MP and P/NEB and 2 units that stopped working. Measurement of MF and MF/NEB could help identify compressors that are likely to fail.

Blow-by as Potential Therapy for Uncooperative Children: An In-Vitro Study

Blow-by, a common form of nebulizer therapy, in which the device is held away from a child's face, has been dismissed as ineffective because studies have demonstrated incremental aerosol drop-off with increasing distances from the face. Many of these studies do not take into account differences among nebulizer systems. Using common, commercially available nebulizer systems, we defined the interaction of system components (nebulizer type, face mask configuration, and compressor characteristics) on aerosol delivery with and without blow-by. A pediatric model consisting of a ventilated mannequin fitted with a filter (inhaled mass), and 3 commercial nebulizer/compressor/face mask systems (Pari Sprint, Respironics Sidestream, and Salter 8900) were used to nebulize budesonide (1.0 mg/2 mL) at 0, 2, and 4 cm from the face. Inhaled mass and the deposition on face, eyes, and mask were measured using high-performance liquid chromatography and reported as a percent of nebulizer charge. At 0 cm, inhaled mass for the Pari, Respironics, and Salter systems was 5.33%, 1.14%, and 3.50%, respectively; at 4 cm from the face, inhaled mass decreased to 1.83%, 0.13%, and 1.14%. Facial (1.12%, 0.63%, and 2.94%) and eye (0.35%, 0.12%, and 0.68%) deposition varied significantly. Pari compressor/nebulizer flow rate was lower than Respironics and Salter (3.5 L/min vs 5.7 L/min and 5.9 L/min), resulting in longer run time (7.7 min vs 4.0 min and 5.3 min). At 4 cm, the Pari system delivered more drug than Respironics at 0 cm, suggesting adequate therapy during blow-by for some systems. Our results indicate that pediatric aerosol delivery is a strong function of the nebulizer system as a whole, and not simply a function of blow-by distance from the face or nebulizer efficiency. In uncooperative children, blow-by can be an effective means of drug delivery with the appropriate nebulizer system.

New approach for particulate exposure monitoring: determination of inhaled particulate mass by 24 h real-time personal exposure monitoring

The objectives of this study were to measure particulate pollution (PM(10), PM(2.5), and PM(1.0)) continuously (24 h/day for 7 day) using real-time exposure monitoring and to estimate total inhalation mass using breathing rate and time-activity. Breathing rates were calculated from measured heart rates. Participants were asked to record a time-activity diary every 15 min. Five microenvironments were defined based on the time-activity diary: home, workplace/school, other indoor, outdoor, and transportation. The average masses of inhaled PM(10) were 530, 316, and 280 μg/day for two office workers, a housewife, and three students, respectively; those of PM(2.5) were 316, 279, and 210 μg/day; and those of PM(1.0) were 251, 264, and 187 μg/day, respectively. We found that home and office/school microenvironments were the main contributors of PM(10), PM(2.5), and PM(1.0) inhaled mass during weekdays and weekends because dwelling time was a determinant factor for inhaled mass. Considering microenvironmental concentration, breathing rate, and dwelling time in each microenvironment, indoor home microenvironments were the largest source of particulate inhalation, followed in order by workplace, transportation, other indoor, and outdoor microenvironments. 34.6% and 69.6% of PM(10) inhalation mass were accumulated in home microenvironments during weekdays and weekends, respectively. The inhaled mass of particulate <1.0 μm (PM(1.0)) in size occupied largest, followed in order by particulate 10-2.5 μm (coarse particle) and 2.5-1.0 μm in size for all occupations.

Facial and Ocular Deposition of Nebulized Budesonide: Effects of Face Mask Design

In vivo case reports and in vitro studies have indicated that aerosol therapy using face masks can result in drug deposition on the face and in the eyes, and that face mask design may affect drug delivery. To test different mask/nebulizer combinations for budesonide, a nebulized steroid used to treat pediatric patients with asthma. Using high-performance liquid chromatography, drug delivery (inhaled mass), facial, and ocular deposition of budesonide aerosols were studied in vitro using a ventilated face facsimile (tidal volume, 50 mL; rate, 25 breaths/min, duty cycle 0.4), a tight-fitting test mask, a standard commercial mask, and a prototype mask designed to optimize delivery by reducing particle inertia. Nebulizer insertion into the mask (front loaded vs bottom loaded) was also tested. Particle size was measured by cascade impaction. Pari LC Plus (PARI Respiratory Equipment; Midlothian, VA) and MistyNeb (Allegiance; McGaw Park, IL) nebulizers were tested. Inhaled mass for tight-fitting and prototype masks was similar (13.2 +/- 1.85% vs 14.4 +/- 0.67% [percentage of nebulizer charge], p = 0.58) and significantly greater than for the commercial mask (3.03 +/- 0.26%, p = 0.005). Mask insertion of nebulizer was a key factor (inhaled mass: front loaded vs bottom loaded, 8.23 +/- 0.18% vs 3.03 +/- 0.26%; p = 0.005). Ocular deposition varied by an order of magnitude and was a strong function of mask design (4.77 +/- 0.24% vs 0.35 +/- 0.05%, p = 0.002, tight fitting vs prototype). Particle sizes (7.3 to 9 microm) were larger than previously reported for budesonide. For pediatric breathing patterns, mask design is a key factor defining budesonide delivery to the lungs, face, and eyes. Front-loaded nebulizer mask combinations are more efficient than bottom-loaded systems.

Jet Nebulizers versus Pressurized Metered Dose Inhalers with Valved Holding Chambers: Effects of The Facemask on Aerosol Delivery

The delivery of an aerosolized drug to a child is a complex process requiring an interaction between parent, child, and inhalation device. Recent studies have shown that the facemask can be a key factor affecting aerosol delivery, particularly the influence of leaks between the facemask and the face. To further quantify these effects and design around them, we have developed a bench model consisting of a breathing simulator, an inhaled mass filter, and a "pediatric face." This paper reviews the development of this model and details important decisions made in its configuration, particularly inhaled mass filter location (e.g., between device and facemask, or in mouth) and mouth diameter (4 or 18 mm). With the final design, we used the model to measure the impact of the "blow-by" technique on nebulizer inhaled mass. In a separate series of experiments, we studied the effects of a "crying" pediatric breathing pattern on inhaled mass for both nebulizers and pressurized metered dose inhalers with valved holding chambers (pMDI VHCs). Results indicated that the location of the inhaled mass filter was a critical factor in assessing aerosol delivery through facemasks and that the "mouth diameter" was not an important variable. Failure to locate the filter in the mouth behind the face, especially for jet nebulizers, failed to accurately measure effects of the facemask and significantly overestimated aerosol delivery. Blow-by results indicated that a 1-cm gap between the facemask and the face was not critical when using a front-loaded facemask. Finally, even with optimal design, the combination of an aerosol generator and facemask with a crying breathing pattern reduced the inhaled mass to 1% of the label dose.

Variation in Pediatric Aerosol Delivery: Importance of Facemask

We have quantified in vitro the influence of the facemask on the amount of drug delivered (e.g., inhaled mass) by jet nebulizer and pressurized metered dose inhaler (pMDI) valved holding chamber (VHC) combinations (non-detergent-coated and detergent-coated). Pediatric breathing patterns were used with a breathing simulator, which was connected to a face onto which each device was positioned. An inhaled mass filter interposed between the simulator and the face captured the aerosolized drug. Budesonide inhalation suspension (0.25 mg) was used with the jet nebulizers and fluticasone propionate (220 microg) pMDI with the VHCs. Maximal drug delivery was measured using constant flow through each device. Breathing pattern effects were assessed for sealed devices (no leaks) and with facemasks (possible leaks at the facemask). Inhaled mass from both nebulizers and pMDI VHCs was affected by breathing pattern, but compared to nebulizers the pMDI VHCs were significantly more variable and sensitive to several factors. The influence of VHC conditioning combined with effects of breathing pattern resulted in the inhaled mass ranging from 0.7 +/- 0.5 to 53.3 +/- 6.2%. Nebulizers were less variable (9.6 +/- 0.7 to 24.3 +/- 3.1%). Detergent coating of VHC markedly increased the inhaled mass and reproducibility of drug delivery (27.2 +/- 1.4 to 53.3 +/- 6.2%) for pMDI VHC combinations, but these effects were lost in the presence of facemasks. Using pediatric patterns of breathing, nebulizer/facemask combinations delivered 4.1 +/- 0.8 to 19.3 +/- 2.3% of the label dose while pMDI and detergent-coated VHC delivered 4.0 +/- 1.6 to 28.6 +/- 2.5%. Facemask seal is a key factor in drug delivery. Leaks around the facemask reduce drug delivery and for pMDI VHCs can negate effects of detergent coating.

In vitro comparison of an electronic micropump and jet nebulizer with budesonide

RATIONALE: Budesonide was approved for use with jet nebulizers. The Aeroneb® Go Nebulizer (Aerogen, Inc.) generates aerosol using the OnQ™ electronic micropump. To determine capabilities of this newer technology, we compared nebulization of budesonide respules 0.5 mg / 2.0mL (AstraZeneca) with the Go and the LC Plus® (Pari, Inc.). METHODS: : Inhaled mass of budesonide was collected on a filter placed between the nebulizer and breathing simulator (Hans Rudolph; adult pattern). Aerosol mass median aerodynamic diameter (MMAD), Geometric Standard Deviation (GSD) and fine particle fraction less than 5.8 μm (FPF) were determined by cascade impaction (Anderson Mk II). Three units of each device were tested in triplicate. Drug deliuvery determined by HPLC. RESULTS: The MMAD (μm) ± GSD of the Go (3.1 ± 1.6) was less than the LC Plus (3.8 + 1.7). Inhaled mass for the Aeroneb Go was 115±13 μg (22±3% of dose) and 91± 14 (18 ± 3% of dose) for the LC Plus (p=0.03:ANOVA). Respirable mass (inhaled mass x FPF) was greater for the Go (20±2 %) than the LC Plus (13±1 %) (p=0.001). Treatment time was 6 min for the Go and 5 min for the LC Plus. CONCLUSIONS: Aerosol delivery of budesonide suspension by the electronic micropump (Aeroneb Go) was similar to the most efficient jet nebulizer (LC Plus). Although budesonide is approved only for use with jet nebulizers, the Aeroneb Go delivered higher inhaled and respirable mass in this in vitro model.

In Vitro Determination of Inhaled Mass and Particle Distribution for Budesonide Nebulizing Suspension

ABSTRACT Nebulized delivery of aerosols to the lung is a complex process dependent on the device, the drug preparation, the patient's breathing pattern and other factors. It is difficult to predict drug delivery in advance and most delivery systems are studied empirically on the bench. To standardize the delivery of aerosolized budesonide suspension, we measured the quantity of drug delivered to the patient mouthpiece using a piston pump as a model of patient breathing and absolute filters. The mass of aerosol at the mouthpiece (the inhaled mass) was determined by high-pressure liquid chromatography (HPLC). The aerodynamic properties of the nebulized budesonide particles were determined by cascade impaction and HPLC. Because the drug is used to treat children, the bench model was based on a pediatric breathing pattern, that is, a tidal volume of 200 mL, a breathing frequency of 25 per minute, and a duty cycle of 0.5. Twenty-seven nebulizer/compressor combinations were studied. Inhaled mass varied over...