Effect of nebuliser and patient interface type on fugitive medical aerosol emissions in adult and paediatric patients.

BACKGROUND: Open circuit aerosol therapy is associated with the potential for fugitive emissions of medical aerosol. Various nebulisers and interfaces are used in respiratory treatments, including the recent consideration of filtered interfaces. This study aims to quantify fugitive medical aerosols from various nebuliser types, in conjunction with different filtered and non-filtered interfaces. METHODS: For both simulated adult and paediatric breathing, four nebuliser types were assessed including; a small volume jet nebuliser (SVN), a breath enhanced jet nebuliser (BEN), a breath actuated jet nebuliser (BAN) and a vibrating mesh nebuliser (VMN). A combination of different interfaces were used including filtered and unfiltered mouthpieces, as well as open, valved and filtered facemasks. Aerosol mass concentrations were measured using an Aerodynamic Particle Sizer at 0.8 m and 2.0 m. Additionally, inhaled dose was assessed. RESULTS: Highest mass concentrations recorded were 214 (177, 262) µg m-3 at 0.8 m over 45-minute run. The highest and lowest fugitive emissions were observed for the adult SVN facemask combination, and the adult BAN filtered mouthpiece combination respectively. Fugitive emissions decreased when using breath-actuated (BA) mode compared to continuous (CN) mode on the BAN for the adult and paediatric mouthpiece combination. Lower fugitive emissions were observed when a filtered facemask or mouthpiece was used, compared to unfiltered scenarios. For the simulated adult, highest and lowest inhaled dose were 45.1 (42.6, 45.6)% and 11.0 (10.1,11.9)% for the VMN and SVN respectively. For the simulated paediatric, highest and lowest inhaled dose were 44.0 (42.4, 44.8)% and 6.1 (5.9, 7.0)% for the VMN and BAN CN respectively. Potential inhalation exposure of albuterol was calculated to be up to 0.11 µg and 0.12 µg for a bystander and healthcare worker respectively. CONCLUSION: This work demonstrates the need for filtered interfaces in clinical and homecare settings to minimise fugitive emissions and to reduce the risk of secondary exposure to care givers.

An in vitro study of the effects of respiratory circuit setup and parameters on aerosol delivery during mechanical ventilation.

Introduction: Aerosol therapy is often prescribed concurrently during invasive mechanical ventilation (IMV). This study determines the effects of nebuliser position, circuit humidification source, and most importantly, lung health on the delivery of aerosol in simulated adult and paediatric IMV patients. Furthermore, the influence of closed suction catheters on aerosol delivery is also addressed. Methods: A vibrating mesh nebuliser was used to deliver Albuterol to simulated adult and paediatric IMV patients with differing states of lung health. Four different nebuliser positions and two types of humidification were analysed. Closed suction catheter mounts, a mainstay in IMV therapy, were incorporated into the circuits. The mean ± SD dose of aerosol (%) was assayed from a filter at the distal end of the endotracheal tube. Results: Nebuliser placement and circuit humidification source had no effect on the delivered dose (%) in adults, yet both significantly did in the simulated paediatric patients. The use of closed suction catheter mounts significantly reduced the delivered dose (%) in adults but not in paediatric patients. A simulated healthy lung state generated the largest delivered dose (%), irrespective of nebuliser position in the adult. However, different lung health and nebuliser positions yielded higher delivered doses (%) in paediatrics. Conclusion: Lung health and respiratory circuit composition significantly affect aerosol delivery in both adult and paediatric IMV patients. Nebuliser placement and respiratory circuit humidification source do not affect the delivered dose in adult but do in paediatric IMV patients.

In vitro model for investigating aerosol dispersion in a simulated COVID-19 patient during high-flow nasal cannula treatment.

The use of high-flow nasal cannula in the treatment of COVID-19 infected patients has proven to be a valuable treatment option to improve oxygenation. Early in the pandemic, there were concerns for the degree of risk of disease transmission to health care workers utilizing these treatments that are considered aerosol generating procedures. This study developed an in vitro model to examine the release of simulated patient-derived bioaerosol with and without high-flow nasal cannula at gas flow rates of 30 and 50 L/min. Aerosol dispersion was evaluated at 30 and 90 cm distances. Reduction of transmission risk was assessed using a surgical facemask on the manikin. Results indicated that the use of a facemask facilitated a 94-95% reduction in exhaled aerosol concentration at 30 cm and 22-60% reduction for 90 cm distance across both gas flow rates. This bench study confirms that this in vitro model can be used as a tool to assess the risk of disease transmission during aerosol generating procedures in a simulated patient and to test factors to mitigate the risk.

Development of Inhalable ATRA-Loaded PLGA Nanoparticles as Host-Directed Immunotherapy against Tuberculosis.

Developing new effective treatment strategies to overcome the rise in multi-drug resistant tuberculosis cases (MDR-TB) represents a global challenge. A host-directed therapy (HDT), acting on the host immune response rather than Mtb directly, could address these resistance issues. We developed an HDT for targeted TB treatment, using All Trans Retinoic Acid (ATRA)-loaded nanoparticles (NPs) that are suitable for nebulization. Efficacy studies conducted on THP-1 differentiated cells infected with the H37Ra avirulent Mycobacterium tuberculosis (Mtb) strain, have shown a dose-dependent reduction in H37Ra growth as determined by the BACT/ALERT® system. Confocal microscopy images showed efficient and extensive cellular delivery of ATRA-PLGA NPs into THP-1-derived macrophages. A commercially available vibrating mesh nebulizer was used to generate nanoparticle-loaded droplets with a mass median aerodynamic diameter of 2.13 µm as measured by cascade impaction, and a volumetric median diameter of 4.09 µm as measured by laser diffraction. In an adult breathing simulation experiment, 65.1% of the ATRA PLGA-NP dose was inhaled. This targeted inhaled HDT could offer a new adjunctive TB treatment option that could enhance current dosage regimens leading to better patient prognosis and a decreasing incidence of MDR-TB.

Evaluation of Aerosol Drug Delivery Options during Adult Mechanical Ventilation in the COVID-19 Era.

Drug delivery devices used for aerosol therapy during mechanical ventilation to ease the symptoms of respiratory diseases provide beneficial treatment but can also pose challenges. Reflecting the significant changes in global guidance around aerosol usage and lung-protective ventilation strategies, seen in response to the COVID-19 pandemic, for the first time, we describe the drug delivery performance of commonly used devices under these conditions. Here, vibrating mesh nebuliser (VMN), jet nebuliser (JN) and pressurised metered-dose inhaler (pMDI) performance was assessed during simulated adult mechanical ventilation. Both standard test breathing patterns and those representatives of low tidal volume (LTV) ventilation with concurrent active and passive humidification were investigated. Drug delivery using a VMN was significantly greater than that with a JN and pMDI for both standard and LTV ventilation. Humidification type did not affect the delivered dose across all device types for standard ventilation. Significant variability in the pMDI dosing was evident, depending on the timing of actuation and the adapter type used. pMDI actuation synchronised with inspiration resulted in a higher delivered drug dose. The type of adapter used for pMDI actuation influenced drug delivery, with the highest dose observed using the CombiHaler.

Cellular Immunotherapy and the Lung.

The new era of cellular immunotherapies has provided state-of-the-art and efficient strategies for the prevention and treatment of cancer and infectious diseases. Cellular immunotherapies are at the forefront of innovative medical care, including adoptive T cell therapies, cancer vaccines, NK cell therapies, and immune checkpoint inhibitors. The focus of this review is on cellular immunotherapies and their application in the lung, as respiratory diseases remain one of the main causes of death worldwide. The ongoing global pandemic has shed a new light on respiratory viruses, with a key area of concern being how to combat and control their infections. The focus of cellular immunotherapies has largely been on treating cancer and has had major successes in the past few years. However, recent preclinical and clinical studies using these immunotherapies for respiratory viral infections demonstrate promising potential. Therefore, in this review we explore the use of multiple cellular immunotherapies in treating viral respiratory infections, along with investigating several routes of administration with an emphasis on inhaled immunotherapies.

Cellular Therapy for the Treatment of Paediatric Respiratory Disease.

Respiratory disease is the leading cause of death in children under the age of 5 years old. Currently available treatments for paediatric respiratory diseases including bronchopulmonary dysplasia, asthma, cystic fibrosis and interstitial lung disease may ameliorate symptoms but do not offer a cure. Cellular therapy may offer a potential cure for these diseases, preventing disease progression into adulthood. Induced pluripotent stem cells, mesenchymal stromal cells and their secretome have shown great potential in preclinical models of lung disease, targeting the major pathological features of the disease. Current research and clinical trials are focused on the adult population. For cellular therapies to progress from preclinical studies to use in the clinic, optimal cell type dosage and delivery methods need to be established and confirmed. Direct delivery of these therapies to the lung as aerosols would allow for lower doses with a higher target efficiency whilst avoiding potential effect of systemic delivery. There is a clear need for research to progress into the clinic for the treatment of paediatric respiratory disease. Whilst research in the adult population forms a basis for the paediatric population, varying disease pathology and anatomical differences in paediatric patients means a paediatric-centric approach must be taken.

Fugitive aerosols in the intensive care unit: a narrative review.

The risk of unintended inhalation of fugitive aerosols is becoming a topic of increasing interest in the healthcare arena. These fugitive aerosols may be bioaerosols, generated by the patient themselves through cough or sneeze, or they may be therapeutic medical aerosols, generated by therapeutic medical aerosol generators with the intent of delivery to a specific patient's respiratory tract. This review focus' on therapeutic aerosols in the intensive care unit (ICU) only, those typically generated by nebulisers. In the intensive care environment, patients are generally in receipt of ventilatory support, and the literature suggests that these different support interventions influence fugitive therapeutic medical aerosol emissions in a variety of ways. Predominant ventilatory support interventions include, but are not limited to, invasive mechanical ventilation (MV), non-invasive mechanical ventilation (NIV), high flow nasal therapy (HFNT), and supplemental oxygen delivery in spontaneously breathing patients. Further, factors such as nebuliser type, patient interface, patient breathing pattern, nebuliser position in the patient breathing circuit and medication formulation characteristics also have been shown to exert influence on aerosol concentrations and distance from the source. Here we present the state of the art knowledge in this, as yet, poorly described field of research, and identify the key risks, and subsequently, opportunities to mitigate the risks of unintended exposure of both patients and bystanders during and for periods following the administration of therapeutic aerosols.

Evaluation of Aerosol Therapy during the Escalation of Care in a Model of Adult Cystic Fibrosis.

Lung disease is the main cause of morbidity and mortality in cystic fibrosis (CF). CF patients inhale antibiotics regularly as treatment against persistent bacterial infections. The goal of this study was to investigate the effect of clinical intervention on aerosol therapy during the escalation of care using a bench model of adult CF. Droplet size analysis of selected antibiotics was completed in tandem with the delivered aerosol dose (% of total dose) assessments in simulations of various interventions providing oxygen supplementation or ventilatory support. Results highlight the variability of aerosolised dose delivery. In the homecare setting, the vibrating mesh nebuliser (VMN) delivered significantly more than the jet nebuliser (JN) (16.15 ± 0.86% versus 6.51 ± 2.15%). In the hospital setting, using VMN only, significant variability was seen across clinical interventions. In the emergency department, VMN plus mouthpiece (no supplemental oxygen) was seen to deliver (29.02 ± 1.41%) versus low flow nasal therapy (10 L per minute (LPM) oxygen) (1.81 ± 0.47%) and high flow nasal therapy (50 LPM oxygen) (3.36 ± 0.34%). In the ward/intensive care unit, non-invasive ventilation recorded 19.02 ± 0.28%, versus 22.64 ± 1.88% of the dose delivered during invasive mechanical ventilation. These results will have application in the design of intervention-appropriate aerosol therapy strategies and will be of use to researchers developing new therapeutics for application in cystic fibrosis and beyond.

In vitro evaluation of disposable transport ventilators with combination aerosol therapy.

BACKGROUND: The COVID-19 pandemic has highlighted the need for alternative short-term, reliable means to aid in the treatment of patients requiring ventilatory support. Concurrent aerosol drug delivery is often prescribed to such patients. As such, this study examines one such short-term option, the disposable gas-powered transport ventilator to effectively deliver aerosol therapy. Factors such as aerosol generator type, patient breathing pattern, humidification and nebuliser position within the respiratory circuit were also examined. METHODS: Aerosol drug delivery characterisation was undertaken using two different disposable transport ventilators (DTVs). Two different nebuliser types, a closed circuit vibrating mesh nebuliser (VMN) and an open circuit jet nebuliser (JN), at different locations in a respiratory circuit, proximal and distal to an endotracheal tube (ETT), with and without passive humidification, were evaluated in simulated adult and paediatric patients. RESULTS: Placement of a nebuliser proximal to the ETT (VMN: 25.19%-34.15% and JN: 3.14%-8.92%), and the addition of a heat and moisture exchange filter (VMN: 32.37%-40.43% and JN: 5.60%-9.91%) resulted in the largest potential lung dose in the adult patient model. Irrespective of nebuliser position and humidification in the respiratory circuit, use of the VMN resulted in the largest potential lung dose (%). A similar trend was recorded in the paediatric model data, where the largest potential lung dose was recorded with both nebuliser types placed proximal to the ETT (VMN: 8.12%-10.89% and JN: 2.15%-3.82%). However, the addition of a heat and moisture exchange filter had no statistically significant effect on the potential lung dose (%) a paediatric patient would receive (p>>0.05). CONCLUSIONS: This study demonstrates that transport ventilators, such as DTVs, can be used concurrently with aerosol generators to effectively deliver aerosolised medication in both adult and paediatric patients.

Nebuliser Type Influences Both Patient-Derived Bioaerosol Emissions and Ventilation Parameters during Mechanical Ventilation.

COVID-19 may lead to serious respiratory complications which may necessitate ventilatory support. There is concern surrounding potential release of patient-derived bioaerosol during nebuliser drug refill, which could impact the health of caregivers. Consequently, mesh nebulisers have been recommended by various clinical practice guidelines. Currently, there is a lack of empirical data describing the potential for release of patient-derived bioaerosol during drug refill. This study examined the release of simulated patient-derived bioaerosol, and the effect on positive end expiratory pressure during nebuliser refill during mechanical ventilation of a simulated patient. During jet nebuliser refill, the positive end expiratory pressure decreased from 4.5 to 0 cm H2O. No loss in pressure was noted during vibrating mesh nebuliser refill. A median particle number concentration of 710 particles cm-3 above ambient was detected when refilling the jet nebuliser in comparison to no increase above ambient detected when using the vibrating mesh nebuliser. The jet nebuliser with the endotracheal tube clamped resulted in 60 particles cm-3 above ambient levels. This study confirms that choice of nebuliser impacts both the potential for patient-derived bioaerosol release and the ability to maintain ventilator circuit pressures and validates the recommended use of mesh nebulisers during mechanical ventilation.

Investigation of the Quantity of Exhaled Aerosols Released into the Environment during Nebulisation.

BACKGROUND: Secondary inhalation of medical aerosols is a significant occupational hazard in both clinical and homecare settings. Exposure to fugitive emissions generated during aerosol therapy increases the risk of the unnecessary inhalation of medication, as well as toxic side effects. METHODS: This study examines fugitively-emitted aerosol emissions when nebulising albuterol sulphate, as a tracer aerosol, using two commercially available nebulisers in combination with an open or valved facemask or using a mouthpiece with and without a filter on the exhalation port. Each combination was connected to a breathing simulator during simulated adult breathing. The inhaled dose and residual mass were quantified using UV spectrophotometry. Time-varying fugitively-emitted aerosol concentrations and size distributions during nebulisation were recorded using aerodynamic particle sizers at two distances relative to the simulated patient. Different aerosol concentrations and size distributions were observed depending on the interface. RESULTS: Within each nebuliser, the facemask combination had the highest time-averaged fugitively-emitted aerosol concentration, and values up to 0.072 ± 0.001 mg m-3 were recorded. The placement of a filter on the exhalation port of the mouthpiece yielded the lowest recorded concentrations. The mass median aerodynamic diameter of the fugitively-emitted aerosol was recorded as 0.890 ± 0.044 µm, lower the initially generated medical aerosol in the range of 2⁻5 µm. CONCLUSIONS: The results highlight the potential secondary inhalation of exhaled aerosols from commercially available nebuliser facemask/mouthpiece combinations. The results will aid in developing approaches to inform policy and best practices for risk mitigation from fugitive emissions.

A compact high resolution flat panel PET detector based on the new 4-side buttable MPPC for biomedical applications.

Compact high-resolution panel detectors using virtual pinhole (VP) PET geometry can be inserted into existing clinical or pre-clinical PET systems to improve regional spatial resolution and sensitivity. Here we describe a compact panel PET detector built using the new Though Silicon Via (TSV) multi-pixel photon counters (MPPC) detector. This insert provides high spatial resolution and good timing performance for multiple bio-medical applications. Because the TSV MPPC design eliminates wire bonding and has a package dimension which is very close to the MPPC's active area, it is 4-side buttable. The custom designed MPPC array (based on Hamamatsu S12641-PA-50(x)) used in the prototype is composed of 4 × 4 TSV-MPPC cells with a 4.46 mm pitch in both directions. The detector module has 16 × 16 lutetium yttrium oxyorthosilicate (LYSO) crystal array, with each crystal measuring 0.92 × 0.92 × 3 mm3 with 1.0 mm pitch. The outer diameter of the detector block is 16.8 × 16.8 mm2. Thirty-two such blocks will be arranged in a 4 × 8 array with 1 mm gaps to form a panel detector with detection area around 7 cm × 14 cm in the full-size detector. The flood histogram acquired with Ge-68 source showed excellent crystal separation capability with all 256 crystals clearly resolved. The detector module's mean, standard deviation, minimum (best) and maximum (worst) energy resolution were 10.19%, +/-0.68%, 8.36% and 13.45% FWHM, respectively. The measured coincidence time resolution between the block detector and a fast reference detector (around 200 ps single photon timing resolution) was 0.95 ns. When tested with Siemens Cardinal electronics the performance of the detector blocks remain consistent. These results demonstrate that the TSV-MPPC is a promising photon sensor for use in a flat panel PET insert composed of many high resolution compact detector modules.