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.

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.

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.

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.

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.

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.

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.

A new system for understanding nebulizer performance.

We have developed a conceptual and mathematical model for nebulizer performance that attempts to provide a unifying theoretical framework for subsequent in vitro studies. Specifically, we have created a lexicon and a way to describe the effects of a standardized breathing pattern for evaluating small-volume jet nebulizers. This model should help researchers communicate more clearly and study planners to design experiments whose data may be more comparable and thus amenable to meta-analysis.

Respiratory care protocol development and impact.

Respiratory care (RC) protocols are widely regarded as the most appropriate method for properly allocating and delivering most forms of respiratory therapy. The use of protocols has increased steadily over the past 15 years, but, despite the successes and modest implementation of RC protocols across the country, there is room for improvement in adopting RC protocols for the effective use of respiratory care services. It also seems that many physicians have yet to be won over, and RC managers need to take the first step toward protocol development and implementation. This article addresses some of the issues surrounding the development of respiratory care protocols and the impact that their implementation may have based on experience gained to date.