External Jet Nebulization and Measured Ventilator Performance.

BACKGROUND: During invasive ventilation, external flow jet nebulization results in increases in displayed exhaled tidal volumes (VT). We hypothesized that the magnitude of the increase is inaccurate. An ASL 5000 simulator measured ventilatory parameters over a wide range of adult settings: actual VT, peak inspiratory pressure (PIP), and time to minimum pressure. METHODS: Ventilators with internal and external flow sensors were tested by using a variety of volume and pressure control modes (the target VT was 420 mL). Patient conditions (normal, COPD, ARDS) defined on the ASL 5000 were assessed at baseline and with 3.5 or 8 L/min of added external flow. Patient-triggering was assessed by reducing muscle effort to the level that resulted in backup ventilation and by changing ventilator sensitivity to the point of auto-triggering. RESULTS: Results are reported as percentage change from baseline after addition of 3.5 or 8 L/min external flow. For ventilators with internal flow sensors, changes in displayed exhaled VT ranged from 10% to 118%, however, when using volume control, actual increases in actual VT and PIP were only 4%-21% (P = .063, .031) and 6%-24% (P = .25, .031), respectively. Changes in actual VT correlated closely with changes in PIP (P < .001; R2 = 0.68). For pressure control, actual VT decreased by 3%-5% (P = .031) and 4%-9% (P = .031) with 3.5 and 8 L/min respectively, PIP was unchanged. With external flow sensors at the distal Y-piece junction, volume and pressure changes were statistically insignificant. The time to minimum pressure increased at most by 8% (P = .02) across all modes and ventilators. The effects on muscle pressure were minimal (∼1 cm H2O), and ventilator sensitivity effects were nearly undetectable. CONCLUSIONS: External flow jet nebulization resulted in much smaller changes in volume than indicated by the ventilator display. Statistically significant effects were confined primarily to machines with internal flow sensors. Differences approached the manufacturer-reported variation in ventilator baseline performance. During nebulizer therapy, effects on VT can be estimated at the bedside by monitoring PIP.

In Vivo Deposition of High-Flow Nasal Aerosols Using Breath-Enhanced Nebulization.

Aerosol delivery using conventional nebulizers with fixed maximal output rates is limited and unpredictable under high-flow conditions. This study measured regulated aerosol delivery to the lungs of normal volunteers using a nebulizer designed to overcome the limitations of HFNC therapy (i-AIRE (InspiRx, Inc., Somerset, NJ, USA)). This breath-enhanced jet nebulizer, in series with the high-flow catheter, utilizes the high flow to increase aerosol output beyond those of conventional devices. Nine normal subjects breathing tidally via the nose received humidified air at 60 L/min. The nebulizer was connected to the HFNC system upstream to the humidifier and received radio-labeled saline as a marker for drug delivery (99mTc DTPA) infused by a syringe pump (mCi/min). The dose to the subject was regulated at 12, 20 and 50 mL/h. Rates of aerosol deposition in the lungs (µCi/min) were measured via a gamma camera for each infusion rate and converted to µg NaCl/min. The deposition rate, as expressed as µg of NaCl/min, was closely related to the infusion rate: 7.84 ± 3.2 at 12 mL/h, 43.0 ± 12 at 20 mL/h and 136 ± 45 at 50 mL/h. The deposition efficiency ranged from 0.44 to 1.82% of infused saline, with 6% deposited in the nose. A regional analysis indicated peripheral deposition of aerosol (central/peripheral ratio 0.99 ± 0.27). The data were independent of breathing frequency. Breath-enhanced nebulization via HFNC reliably delivered aerosol to the lungs at the highest nasal airflows. The rate of delivery was controlled simply by regulating the infusion rate, indicating that lung deposition in the critically ill can be titrated clinically at the bedside.

In Vitro Model for Analysis of High-Flow Aerosol Delivery During Continuous Nebulization.

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.

Enhanced Aerosol Delivery During High-Flow Nasal Cannula Therapy.

BACKGROUND: Aerosolized drug delivery via high-flow nasal cannula (HFNC) decreases as gas flow is increased. To improve aerosol delivery, breath-enhanced jet nebulizer may increase aerosol output. This study tested that hypothesis and compared breath-enhanced jet nebulizer to vibrating mesh nebulizer technology. METHODS: First, in an isolated circuit, breath-enhanced jet nebulizer and vibrating mesh nebulizer aerosol outputs were measured during simulated HFNC by using infused saline solution at rates of 5-60 mL/h. Limits were defined when nebulizer filling was detected. The devices were then tested by using 99mTc/saline solution to measure maximum rates of aerosol production. After the output experiments, drug delivery was measured in vitro by using a model that consisted of an HFNC circuit interfaced to a realistic 3-dimensional printed head. The 99mTc/saline solution was infused at rates of 5 to 60 mL/h for the breath-enhanced jet nebulizer and 5 to 20 mL/h for the vibrating mesh nebulizer with HFNC gas flows of 10 to 60 L/min. Aerosol delivery to the trachea was measured by using a shielded ratemeter, which defined the rate of drug delivery (µg NaCl/min). RESULTS: With increasing gas flow, breath-enhanced jet nebulizer output increased to a maximum of 50 mL/h, the vibrating mesh nebulizer maximum was 12 mL/h. At HFNC gas flow of 60 L/min, breath-enhanced jet nebulizer delivered 3.16 to 316.8 µg NaCl/min, the vibrating mesh nebulizer delivered 23.5 to 61.7 µg NaCl/min. For infusion pump flows of 5 to 12 mL/h, the rate of drug delivery was independent of nebulizer type (P = .19) and dependent on infusion pump flow (P < .001) and gas flow (P < .001). CONCLUSIONS: Increasing gas flow increased breath-enhanced jet nebulizer output, which demonstrated the effects of breath enhancement. At 60 L/min, breath enhanced jet nebulizer delivered up to 5 times more aerosol compared with conventional vibrating mesh nebulizer technology. Breath-enhanced jet nebulizer delivered a wide range of dose rates at all high flows. In patients who are critically ill, breath-enhanced jet nebulizer technology may allow titration of bedside dosing based on clinical response by simple adjustment of the infusion rate.

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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Continuous infusion aerosol delivery of prostacyclins during mechanical ventilation: challenges, limitations, and recent advances.

INTRODUCTION: Critically ill mechanically ventilated patients routinely receive aerosol delivery of epoprostenol by continuous infusion of the nebulizer by syringe pump. This procedure is 'off-label' as no FDA approved drug presently exists. Without standardized protocols, therapy is based on prior experience with bronchodilators, limited studies of delivery systems and anecdotal clinical trials. Current protocols based upon patient body weight and drug concentration determines the infusion rate of drug dose delivered to the nebulizer , which is only distantly related to dose delivered to the lung and may be altered by many factors. AREAS COVERED: This paper reviews the background of this technique as well as current methods of managing drug delivery, technical challenges, and limitations. A recent advance in aerosol laboratory bench testing, using radiolabeled aerosols, is presented to reveal important factors defining delivery. EXPERT OPINION: Off-label use of continuously nebulized prostacyclin in the ICU lacks the support of large clinical trials needed for FDA clearance. However, comprehensive bench studies afford the potential for clinicians to better understand and manage therapy at a level above simple dosing of the nebulizer by body weight. New research techniques are enhancing our basic comprehension of the interaction between aerosol devices and the mechanical ventilator.

The Unfulfilled Promise of Inhaled Therapy in Ventilator-Associated Infections: Where Do We Go from Here?

Respiratory infection is common in intubated/tracheotomized patients and systemic antibiotic therapy is often unrewarding. In 1967, the difficulty in treating Gram-negative respiratory infections led to the use of inhaled gentamicin, targeting therapy directly to the lungs. Fifty-three years later, the effects of topical therapy in the intubated patient remain undefined. Clinical failures with intravenous antibiotics persist and instrumented patients are now infected by many more multidrug-resistant Gram-negative species as well as methicillin-resistant Staphylococcus aureus. Multiple systematic reviews and meta-analyses suggest that there may be a role for inhaled delivery but "more research is needed." Yet there is still no Food and Drug Administration (FDA) approved inhaled antibiotic for the treatment of ventilator-associated infection, the hallmark of which is the foreign body in the upper airway. Current pulmonary and infectious disease guidelines suggest using aerosols only in the setting of Gram-negative infections that are resistant to all systemic antibiotics or not to use them at all. Recently two seemingly well-designed large randomized placebo-controlled Phase 2 and Phase 3 clinical trials of adjunctive inhaled therapy for the treatment of ventilator-associated pneumonia failed to show more rapid resolution of pneumonia symptoms or effect on mortality. Despite evolving technology of delivery devices and more detailed understanding of the factors affecting delivery, treatment effects were no better than placebo. What is wrong with our approach to ventilator- associated infection? Is there a message from the large meta-analyses and these two large recent multisite trials? This review will suggest why current therapies are unpredictable and have not fulfilled the promise of better outcomes. Data suggest that future studies of inhaled therapy, in the milieu of worsening bacterial resistance, require new approaches with completely different indications and endpoints to determine whether inhaled therapy indeed has an important role in the treatment of ventilated patients.

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.

Control de la fuente respiratoria mediante el uso de una mascarilla quirúrgica: un estudio in vitro.

RESUMENLa etiqueta para la tos y la higiene respiratoria son formas de control de la fuente de emisión cuyo uso se alienta para evitar la propagación de infecciones respiratorias. El uso de mascarillas quirúrgicas como medio de control de la fuente en términos de reducción de la exposición de terceros no se ha investigado. En este estudio diseñamos un modelo in vitro utilizando varias mascarillas faciales con el fin de evaluar su aporte a la reducción de la exposición cuando son utilizadas en la fuente infecciosa (Fuente) en comparación con la reducción proporcionada por las mascarillas usadas para la protección primaria (Receptor), así como los factores que contribuyen a cada una. En una cámara con diversos flujos de aire se exhalaron aerosoles radiomarcados desde una cabeza de maniquí de cara blanda ventilada, utilizando respiración periódica y tos (Fuente). En otro maniquí, al que se le colocó un filtro, se cuantificó la exposición del Receptor. Se probaron una mascarilla quirúrgica de ajuste natural, una mascarilla quirúrgica de ajuste seguro (SecureFit) y una mascarilla respiratoria autofiltrante de clase N95 (comúnmente conocida como "mascarilla autofiltrante N95") con y sin sello de vaselina. Con la tos, el control de la fuente (mascarilla quirúrgica/autofiltrante colocada en la Fuente) fue estadísticamente superior a la protección brindada por la mascarilla quirúrgica/mascarilla autofiltrante sin sellar en el Receptor (protección del Receptor) en todos los entornos. Para igualar el control de la fuente durante la tos, la mascarilla autofiltrante N95 debe estar sellada con vaselina. Durante la respiración periódica, el control de la fuente fue comparable o superior a la protección brindada por la mascarilla quirúrgica/autofiltrante en el Receptor. El control de la fuente mediante mascarillas quirúrgicas puede ser una importante defensa adicional contra la propagación de infecciones respiratorias. El ajuste de la mascarilla quirúrgica/autofiltrante combinado con los patrones de flujo de aire en un entorno determinado contribuye de manera significativa a la eficacia del control de la fuente. Los futuros ensayos clínicos deberían incluir un brazo de control de la fuente con mascarilla quirúrgica a fin de evaluar el aporte realizado por el control de la fuente a la protección general contra infecciones de transmisión aérea.

Face Mask Leak Determines Aerosol Delivery in Noninvasive Ventilation.

BACKGROUND: Aerosol transport during noninvasive ventilation follows the flow of pressurized gas through the noninvasive ventilation circuit, vented via leak port and face mask, and inhaled by the patient. Recommendations for nebulizer placement are based on in vitro models that have focused primarily on aerosol losses via the leak port; face mask leaks have been avoided. This study tested aerosol delivery in the setting of controlled face mask leak. METHODS: Three nebulizer technologies were studied on a bench model using a lung simulator with a face mask placed onto a manikin head. Radiolabeled aerosol delivery (ie, inhaled mass) was determined by mass balance using filters and a gamma camera that tested the effects of nebulizer location and face mask leak. Low (15-20 L/min) and high (55-60 L/min) mask leaks were used to mimic realistic clinical conditions. RESULTS: Inhaled mass (% nebulizer charge) was a function of nebulizer technology (with the nebulizer at ventilator outlet position: Aerogen 22.8%, InspiRx 11.1%, and Hudson 8.1%; P = .001). The location of the nebulizer before or after the leak port was not important (P = 0.13 at low leak and P = 0.38 at high leak). Aerosol delivery was minimal with high mask leak (inhaled mass 1.5-7.0%). Aerosol losses at the leak port at low mask leak were 28-36% versus 9-24% at high mask leak. Aerosol losses via the mask leak were 16-20% at low mask leak versus 46-72% at high mask leak. Furthermore, high face mask leak led to significant deposition on the mask and face (eg, up to 50% of the nebulizer charge with the Aerogen mask). CONCLUSIONS: During noninvasive ventilation, nebulizer placement at the ventilator outlet, which is a more practical position, is effective and minimizes deposition on face and mask. Aerosol therapy should be avoided when there is high face mask leak.

Factors Determining Continuous Infusion Aerosol Delivery During Mechanical Ventilation.

BACKGROUND: 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 in vitro. METHODS: Using a bench model of adult mechanical ventilation, radiolabeled saline was infused at 6 flows (1.5-12 mL/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 from 0.13 to 0.34 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 at 3.5 L/min and 50 psi. Infusion time was 1 h. 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. RESULTS: Variation in inhaled mass was significantly explained by pump flow and duty cycle (R2 0.92) 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. CONCLUSIONS: 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; 10-12 mL/h was the maximum infusion flow for both nebulizer technologies.

Reducing Aerosol-Related Risk of Transmission in the Era of COVID-19: An Interim Guidance Endorsed by the International Society of Aerosols in Medicine.

National and international guidelines recommend droplet/airborne transmission and contact precautions for those caring for coronavirus disease 2019 (COVID-19) patients in ambulatory and acute care settings. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, an acute respiratory infectious agent, is primarily transmitted between people through respiratory droplets and contact routes. A recognized key to transmission of COVID-19, and droplet infections generally, is the dispersion of bioaerosols from the patient. Increased risk of transmission has been associated with aerosol generating procedures that include endotracheal intubation, bronchoscopy, open suctioning, administration of nebulized treatment, manual ventilation before intubation, turning the patient to the prone position, disconnecting the patient from the ventilator, noninvasive positive-pressure ventilation, tracheostomy, and cardiopulmonary resuscitation. The knowledge that COVID-19 subjects can be asymptomatic and still shed virus, producing infectious droplets during breathing, suggests that health care workers (HCWs) should assume every patient is potentially infectious during this pandemic. Taking actions to reduce risk of transmission to HCWs is, therefore, a vital consideration for safe delivery of all medical aerosols. Guidelines for use of personal protective equipment (glove, gowns, masks, shield, and/or powered air purifying respiratory) during high-risk procedures are essential and should be considered for use with lower risk procedures such as administration of uncontaminated medical aerosols. Bioaerosols generated by infected patients are a major source of transmission for SARS CoV-2, and other infectious agents. In contrast, therapeutic aerosols do not add to the risk of disease transmission unless contaminated by patients or HCWs.

Comparison of Vibrating Mesh, Jet, and Breath-Enhanced Nebulizers During Mechanical Ventilation.

BACKGROUND: This study compared 3 nebulizer technologies for inter- and intradevice reproducibility, humidification, and fill volume sensitivity during mechanical ventilation: a breath-enhanced jet nebulizer, a vibrating mesh nebulizer, and a jet nebulizer. The breath-enhanced jet nebulizer featured a new design located on the wet side of the humidifier to reduce aerosol loss and potential humidifier contamination. The vibrating mesh nebulizer and the jet nebulizer were placed on the dry side. METHODS: Aerosol delivery was measured using multiple ventilator settings (inspiratory time = 0.45-1.01 s). Using radiolabeled saline and a gamma camera, bench studies were performed using a ventilator to test 4 breathing patterns. Four scenarios were assessed during testing: 3 mL and 6 mL fill volumes with and without heated wire humidification. Measurements included inhaled mass (as a percentage of the nebulizer charge), nebulizer residual, mass balance, and aerosol particle size distribution. Statistics were determined using Mann-Whitney and linear regression. RESULTS: The inhaled mass for the breath-enhanced jet nebulizer was 10.5-29.2% and was affected by fill volume (P = .004) but not by humidity. The inhaled mass for the vibrating mesh nebulizer was 0.9-33% and was unaffected by fill volume and humidity. The inhaled mass for the jet nebulizer was 2.5-25.9% and was affected by both fill volume (P = .009) and humidity (3 mL, P = .002). The inhaled mass for the vibrating mesh nebulizer was more variable due to random failures to achieve complete nebulization, and inhaled mass correlated closely with residual mass: IM% = -0.233(Residual%) + 24.3, r2 = 0.67, P < .001. For all devices, large particles were lost in the ventilator tubing; large particles were also lost in the humidifier for the vibrating mesh nebulizer (17% nebulizer charge), resulting in similar particle distributions (mass median aerodynamic diameter 1.33-1.95 µm) for all devices. CONCLUSIONS: Nebulization with the breath-enhanced jet nebulizer was less sensitive to humidification than the jet nebulizer. Delivery via the vibrating mesh nebulizer was not predictable, with random failure to empty (55% experimental runs). All devices delivered similar particle distributions. Wet-side aerosol delivery avoids humidifier contamination, and breath-enhanced technology can ensure better control of drug delivery.

Wet-Side Breath-Enhanced Jet Nebulization: Controlling Drug Delivery During Mechanical Ventilation.

BACKGROUND: The present study tested a novel nebulizer and circuit that use breath enhancement and breath actuation to minimize ventilator influences. The unique circuit design incorporates "wet-side" jet nebulization (the nebulizer connected to the humidifier outlet port) to prevent unpredictable aerosol losses with active humidification. The system was studied using several ventilator brands over a wide range of settings, with and without humidification. METHODS: During treatment, a 2-position valve directed all ventilator flow to the nebulizer, providing breath enhancement during inspiration. Aerosol was generated by air 50 psi 3.5 L/m triggered during inspiration by a pressure-sensitive circuit. Particles were captured on an inhaled mass filter. Testing was performed by using active humidification or bypassable valved heat and moisture exchanger (HME) over a range of breathing patterns, ventilator modes, and bias flows (0.5-5.0 L/m). The nebulizer was charged with 6 mL of radiolabeled saline solution. Mass balance was performed by using a gamma camera. Tidal volume was monitored by ventilator volume (exhaled VT) and test lung volume. The Mann-Whitney test was used. RESULTS: A total of 6 mL was nebulized within 1 h. Inhaled mass (% neb charge): mean ± SD (all data) 31.1% ± 6.45; no. = 83. Small significant differences were seen with humidification for all modes (humidified 36.1% ± 5.60, no. = 26; bypassable valved HME 28.8% ± 5.51, no. = 57 [P < .001]), continuous mandatory ventilation modes [P < .001], and pressure support airway pressure release ventilation modes [P < .001]. Mass median aerodynamic diameter ranged from 1.04 to 1.34 µm. The VT was unaffected (exhaled VT -5.0 ± 12.9 mL; P = .75) and test lung (test lung volume 25 ± 14.5 mL; P = .13). Bias flow and PEEP had no effect. CONCLUSIONS: Breath enhancement with breath actuation provided a predictable dose at any ventilator setting or type of humidification. Preservation of drug delivery during active humidification is a new finding, compared with previous studies. The use of wall gases and stand alone breath actuation standardizes conditions that drive the nebulizer independent of ventilator design. Wet-side nebulizer placement at the humidifier outlet allows delivery without introducing aerosol into the humidification chamber.

Maximizing Deep Lung Deposition in Healthy and Fibrotic Subjects During Jet Nebulization.

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 26.2% ± 1.83 and in IPF individuals 23.4% ± 1.60 (p = 0.414). Upper airway deposition was 1.4% ± 0.83 and 2.3% ± 0.48, respectively (p = 0.351), 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.

Interferon-γ enhances the antifibrotic effects of pirfenidone by attenuating IPF lung fibroblast activation and differentiation.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) pathogenesis involves multiple pathways, and combined antifibrotic therapy is needed for future IPF therapy. Inhaled interferon-γ (IFN-γ) was recently shown to be safe and without systemic effects in patients with IPF. AIM: To examine the in vitro effects of individual and combined treatment with IFN-γ and pirfenidone (PFD) on normal and IPF fibroblast activation and extracellular matrix remodeling after TGF-ß1 and PDGF-BB stimulation. METHODS: IPF and normal human lung fibroblasts (NHLF) were treated with IFN-γ, PFD or a combination of both drugs in the presence of either TGF-ß1 or PDGF-BB. The effects of TGF-ß1 and PDGF-BB treatment on cell viability, proliferation, differentiation and migration were examined. The expression of collagen 1, matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs) was analyzed using qPCR, Western blotting and gelatin zymography. Total collagen content in conditioned media was also measured using a Sircol assay. RESULTS: Compared to that of PFD, the effect of IFN-γ in downregulating normal and IPF lung fibroblast differentiation to myofibroblasts in response to TGF-ß1 was more potent. Importantly, the combination of IFN-γ and PFD had a possibly synergistic/additive effect in inhibiting the TGF-ß1- and PDGF-BB-induced proliferation, migration and differentiation of normal and IPF lung fibroblasts. Furthermore, both drugs reversed TGF-ß1-induced effects on MMP-1, - 2, - 3, - 7, and - 9, while only PFD promoted TIMP-1 and-2 expression and release. CONCLUSIONS: Our findings demonstrate that the antifibrotic effects of IFN-γ and PFD on normal and IPF lung fibroblasts are different and complementary. Combination therapy with inhaled IFN-γ and PFD in IPF is promising and should be further explored in IPF clinical trials.

Nebulized Mannitol, Particle Distribution, and Cough in Idiopathic Pulmonary Fibrosis.

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.

Repurposing of gamma interferon via inhalation delivery.

Pulmonary diseases frequently involve imbalances in immunity. The inability to control bacteria in tuberculosis is a failed response to a pathogen. Idiopathic pulmonary fibrosis (IPF), a progressive fibrotic lung disease, can lead to respiratory failure and death within 3 years of diagnosis. Chronic obstructive pulmonary disease (COPD) progresses until death and in recent years has been labeled an autoimmune disease. Proposed mechanistic pathways of pathophysiology involve uncontrolled healing governed by pro-fibrotic cytokines that are unresponsive to the standard anti-inflammatory agents (e.g., corticosteroids). Interferon-γ (IFN-γ), currently delivered as a subcutaneous injection for chronic granulomatous disease and osteopetrosis, is a cytokine that can stimulate macrophage function and inhibit fibrotic pathways. In recent studies, our group has repurposed IFN-γ as an inhaled aerosol, targeted directly to the lung to treat a host of diseases affected by dysregulated immunity. At present, we have studied its potential in treating tuberculosis and IPF. In a controlled clinical trial in tuberculosis, inhaled IFN-γ was effective while parenteral IFN-γ was not, indicating that macrophages can be effectively immune-stimulated by aerosol therapy. A similar approach has been taken in IPF. In a two-year safety study treating patients with IPF, the drug was safe and the pretreatment decline in pulmonary function was reversed. Furthermore, the same fibrotic pathways active in the lung parenchyma in IPF may be at fault in the airways of COPD patients. These experiences warrant the continued evaluation of inhaled IFN-γ in human clinical trials.