Slow Inhalation Research Articles

599. ASSESSMENT OF BREATHING MECHANICS IN OESOPHAGEAL CANCER SURVIVORS USING A 3D-MOTION CAPTURE SYSTEM

Abstract Background Traditional open surgery is characterised by an intercostal incision. The associated ribcage injury may precipitate the development of post-thoracotomy-related pain, with impaired respiratory muscle contraction, leading to compromised coughing and decreased lung volumes. These changes in breathing mechanics may precipitate pulmonary complications, occurring in up to 40% of the patients. There is however no data available on the long-term breathing function and its implications on the health-related quality of life following oesophagectomy. This proof-of-concept study aimed to objectively measure breathing movements using a 3D-motion capture system and to understand the impact of surgery on breathing patterns in oesophageal cancer survivors. Methods Oesophageal cancer survivors who were disease-free for at least 1 year postoperatively and healthy controls were included. Participants completed quality-of-life (QoL) questionnaires, including EORTC QLQ-C30, -OG25 and LASORS. Eighty-nine retroreflective markers were affixed to the participants' trunks to measure respiratory movements via the Vicon motion capture system during handheld spirometry performance. The highest spirometry value was recorded for the slow inspiratory (SIVC) and forced expiratory vital capacity (FEVC). Concurrent movement data was obtained from adjacent surface markers connected to the midpoint, allowing evaluation of the total volumetric movement of the trunk, and thoracic and abdominal contributions. Results Eighteen patients (median age 68) and 22 controls (median age 29) were included. Patients exhibited a significantly reduced SIVC alongside decreased chest movement contribution (median 2.4519 litres IQR 0.9270) compared to controls (median 3.1492 litres, IQR 1.8381) (p=0.013). Meanwhile, patients also had significantly lower FEVC with lower abdominal movement (median 1.5134 litres, IQR 0.7852) compared to controls (median 2.1263 litres, IQR 0.8740) (p=0.039). The QoL amongst patients was significantly worse for half of the EORTC domains, including physical functioning, fatigue, dyspnoea, pain and discomfort, and coughing (p<0.05). Additionally, the QoL of patients was consistently lower across all LASOR domains (p<0.05). Conclusion Current data showed lower spirometry parameters and breathing movements amongst oesophageal cancer survivors, suggestive of impaired breathing mechanics. Specifically, chest expansion was compromised during slow inhalation, while abdominal contraction was reduced during forced exhalation. These findings suggest restrictive changes in breathing mechanics

In Vitro Regional Deposition of Nasal Sprays in an Idealized Nasal Inlet: Comparison with In Vivo Gamma Scintigraphy.

To compare in vitro regional nasal deposition measurements using an idealized nasal airway geometry, the Alberta Idealized Nasal Inlet (AINI), with in vivo regional deposition for nasal drug products. One aqueous solution formulation (NasalCrom), one aqueous suspension formulation (Nasonex) and one nasal pressurized metered dose spray device (QNASL) were selected. Two spray orientation angles, 60° and 45° from the horizontal, were selected. A steady inhalation flow rate of 7.5 L/min was selected to simulate slow inhalation through a single nostril. After actuation, the AINI was disassembled. The mass of drug deposited in each region and a downstream filter, representing penetration of drug to the lungs, was determined using ultraviolet-visible (UV-Vis) spectrophotometry. No filter (lung) deposition was detected for NasalCrom or Nasonex. Filter deposition ranged from 6 to 11% for QNASL. For NasalCrom, 45% to 69% of the dose deposited in the AINI was deposited in the vestibule and 31% to 55% was deposited in the turbinates; for Nasonex, 66% to 74% (vestibule) and 26% to 34% (turbinates); for QNASL, 90% to 100% (vestibule) and 0% to 10% (turbinates). No statistically significant difference was observed between regional deposition in vivo and in vitro for any of the formulations, except that nasopharyngeal deposition with Nasonex differed by less than 1.56% from in vivo, which while statistically significant, is unlikely to be clinically significant. The AINI was able to mimic regional in vivo deposition for nasal drug products, permitting differentiation between devices based on regional deposition.

Controlled inhalation improves central and peripheral deposition in cystic fibrosis patients with moderate lung disease.

AimWith progressive impairment of lung function, deposition of inhaled drug in the lungs becomes progressively more central, limiting its effectiveness. This pilot study explored the possibility that long slow inhalations might improve delivery of aerosol to the lung periphery in cystic fibrosis patients with moderate lung disease.MethodsFive subjects aged 12–18 years (mean FEV1 72%; range 63–80%) inhaled a radiolabelled aerosol from a jet nebuliser on two occasions. Two inhalation techniques were compared: breathing tidally from a standard continuous output nebuliser and using long slow inhalations from the AKITA® JET system.ResultsLong slow breaths resulted in much lower oropharyngeal deposition with higher lung doses. Importantly, the peripheral lung increased proportionately. The increased lung dose is attributable to more of the larger inhaled droplets passing into the lower airways. This would be expected to increase the central deposition unless significantly more of the smaller droplets were able to penetrate deeper into the lungs. The data support improved delivery of drug to the distal lung when compared with tidal breathing.ConclusionThese pilot data suggest that this approach may prove to be clinically relevant in improving the efficacy of inhaled medication in those with moderate‐severe lung disease.

The impact of the clip-tone training device and its smartphone application to pressurized metered-dose inhaler in adult asthmatics

Background Despite traditional inhaler technique counseling, many patients make clinically important mistakes when they use their inhalers. This study investigates the value of using a connected inhalation aid when adults with asthma use their metered-dose inhaler (pMDI). Methods Adult asthmatics (n = 221), using a pMDI, were randomly divided into a verbal training group (n = 110) and an enhanced training group (n = 111). 21 subjects were lost during the study, each group included 100 subjects at the end of the study. The study was divided into 3 visits. Traditional pMDI training was delivered at visit 1 to both groups which included an explanation of the steps with special stress on frequently mistaken steps e.g. exhalation before use and inhaling slowly and deeply. The enhanced training group was enhanced by using the Clip-Tone training aid linked to its dedicated smartphone app. enhanced training patients were encouraged to use this connected training aid during real-life use between the study visits. Baseline data were collected at the first visit. At all three visits (baseline, 1 month, and 2 months), subjects first completed all inhaler techniques, health outcome measures, received inhaler training, then took bronchodilators, and 30 min later repeated the lung function outcome measures. Results Both groups showed a significant decrease (p < 0.001) in the total mean number of pMDI inhalation techniques mistakes at visits 2 and 3, with a lower number of mistakes (p < 0.05) for slower inhalations for the enhanced training group compared to the verbal training group. Inhalation time (an indicator of a slow inhalation) significantly (p < 0.05) improved at each visit in the enhanced training group. In the enhanced training group, there was a gradual significant increase (p < 0.05) in lung functions while the improvements in the verbal training group were only significant (p < 0.05) at visit 3, and by visit 3, the enhanced training group had significantly higher scores than the verbal training group on both FEV1 and PEF% predicted. The asthma control test (ACT) score improved at each visit in both groups with a greater increase in the enhanced training group (p < 0.05) and more patients (44 and 21) improved their score by 3 or more in the second and third visit respectively. Conclusion The connected Clip-Tone training aid helped patients improve their pMDI inhaler technique and their asthma control compared to traditional methods. These results highlight the potential of connected inhalers in the future management of inhaled therapy.

Comparative Outcomes of Immunochemotherapy with RCD (rituximab, cyclophosphamide, dexamethasone) and BCD (bortezomib, cyclophosphamide, dexamethasone) in Waldenstrom Macroglobulinaemia: NCT02971982

Objective: To compare the outcomes of immunochemotherapy with rituximab based treatment and bortezomib treatment in pantines with Waldenstrom macroglobulinaemiaMethod: The randomized study enrolling 11eligible patients at first affiliated hospital of Soochow university aged from 44 years old to 71 years old. All of them were diagnosed by bone marrow biopsy, immunofixed electroresis with IgM-M protein and MYD88L265P mutation, all of them had clinical symptoms such as fever, weak, loss of weigh, hemorrhage and so on. These patients with newly diagnosed WM were randomly to two groups to receive treatment. 4 patients were treated by bortezomib, cyclophosphamide and dexamethasone (PCD), the other 7 patients were treated by rituximab, cyclophosphamide and dexamethasone (RCD), the primary end point was overall response rate (ORR), and major response rate (MRR).Results: The median age of 11 patients was 63 years old (range: 44-71 years), with a male to female ratio was 4.5. ALL of them had clinical symptoms, most of them had non-specific symptoms such as weak, fever (36.6%, 4/11), and loss of weight (18.2%, 2/11).One of them had coagulation disorder with retroperitoneal hematoma, and one had rashes. 4 patients treated by PCD received 6 cycles and 7 patients treated by RCD received 3 to 6 cycles (average 5 cycles). The response evaluation is arcaded by the symptoms and M-protein in plasma. All of the clinical symptoms were remitted by treatment in each group after one to four cycles. 9 patients with anemia at first and 88.8% (8/9) were remitted. To evaluate the M-protein, the overall response rate (ORR) of Patients who received PCD treatment is 75% (3/4), and major reaction rate (MRR) (1 patient was PR, 1 patient was VGPR, and 1 patient was CR) is 75%. The ORR of patents received RCD treatment is 42.85% (3/7), and the MRR is 14.28(1 patient reached PR). The two group is not statistical significance in ORR (P=0.554), but the MRR is significantly better in the PCD arm compared with RCD arm (95%CI, 75% to 42.85%, P=0.044).The toxicity of the PCD arm was peripheral neuritis (100%), I to II grade, mostly accrued after 4 cycles of bortezomib, and one of them with dosage reduction to 1.0mg/m2 by bortezomib. The severe adverse event was hepatotoxicity by extending interval treatment of each cycle. The major toxicity of RCD arm was infusion reaction of rituximab (37.1%, 4/7), such as fever, chest congestion and hypoxemia, mostly at first to third cycle. All can be relieved by slow infusion and oxygen inhalation. The incidence rate of toxicity was similar in two groups (P=0.125).Conclusion: Rituximab and Bortezomib are new immunochemotherapy for Waldenstrom macroglobulinaemia, both (combination with other agent) are recommended as a first-line treatment for WM. In our preliminary statistics, both of them had effect, but the MRR is better in PCD group. Bortezomib may can act on the NF-κB cytokine pathway. But our samples were limited, we still need to be confirmed by expanding the samples quantity and extending the time of intervention. DisclosuresNo relevant conflicts of interest to declare.

Advanced counselling using training device and smartphone application on inhalation technique from metered-dose inhaler with spacer equipped with different interfaces in asthmatic children.

Spacers are equipped with either facemask or mouthpiece as an interface through which patient inhale their dose. The present study aimed to evaluate the effect of advanced counselling using training devices and smartphone applications on inhalation techniques from the metered-dose inhaler (MDI) with a spacer equipped with different interfaces. 100 paediatric asthmatic children (8-18 years) were divided into two groups. Group one was a spacer with a mouthpiece (n=50) and group two was a spacer with a facemask group (n=50). Both groups had three visits one month apart. At each visit, patients were asked to show the investigator their inhalation technique using MDI with spacer, and mistakes were recorded and then patients were trained on the proper inhalation technique of using MDI with a spacer. In the spacer with mouthpiece group, Flo-Tone was attached to the mouthpiece to allow the Trainhaler smartphone application to detect the duration of inhalation. In the spacer with facemask group, there was no need to use the Flo-Tone training device since the facemask was equipped with a built-in whistle detected by the Trainhaler smartphone application. The total number of mistakes in the inhalation technique decreased significantly (P<.05) in visits 2 and 3 for both groups. Duration of inhalation increased significantly (P<.05) in the mouthpiece group at visit 2 and in the facemask group at visit 3. Achieving 5 seconds of slow deep inhalation, breath-holding for 5 seconds after inhalation and the tight fit of facemask represented the major obstacles in most children especially the youngest subjects. Breath out as far as comfortable had the highest number of mistakes in the first visit in both groups. The Flo-Tone with its positive reinforcement whistle and the Trainhaler smartphone application significantly improved the inhalation technique by decreasing the total number of mistakes especially in important steps eg, shaking MDI, maintaining slow inhalation rate, breath-holding after inhalation and appropriate facemask fitting. Also, they increased the duration of inhalation of asthmatic children from MDI with a spacer. Both spacer interfaces are easy to handle once taught well.

The effect of Clip-tone® and its smartphone application on optimisation of metered-dose inhalers inhalation technique.

Although metered-dose inhalers (pMDI) therapy is convenient and widely prescribed, its use usually results in repetitive inhalation technique errors. One of the most repetitive errors is inhaling too fast through the pMDI. The present study aimed to evaluate the effect of Clip-tone® along with smartphone visual feedback application on the subject's inhalation time. Two hundred subjects were included in the study. They were randomised into four groups. Group 1 received only verbal counselling; group 2 received verbal counselling with resistance (a modified Clip-tone® that does not produce whistle attached to their pMDI); group 3 received verbal counselling plus whistle (as audio feedback) from ordinary Clip-tone® and group 4 received verbal counselling plus audio feedback (whistle) from Clip-tone® and visual feedback (smartphone application). Inhalation time through the pMDI for each subject was recorded three times and inter and intra-subjects variations were calculated. Verbal counselling plus audio feedback and verbal counselling plus audio and visual feedbacks groups had 45/50 (90%) and 37/50 (74%) subjects respectively, having correct inhalation flow (inhaling at between 3 to 7seconds). Verbal counselling plus audio feedback and verbal counselling plus audio and visual feedbacks groups' inter and intra-subjects variations were lower than that of verbal counselling and verbal counselling with resistance groups which had 28/50 (52%) and 20/50 (40%) subjects respectively, with inhalation time between 3 and 7seconds. Providing audio feedback by the Clip-tone® along with smartphone visual feedback application maintained the deep and slow inhalation through pMDI much better compared to verbal counselling only. We recommend the patients to take all their inhaled doses using pMDI attached to a training device like Clip-tone® along with a smartphone visual feedback application for optimisation of the aerosol delivery from the pMDI.

Recrutamento alveolar com suspiro: impacto na mecânica respiratória e oxigenação de pacientes ventilados mecanicamente

INTRODUÇÃO: O suspiro caracteriza-se pela realização de uma inspiração lenta e profunda, seguida de uma expiração lenta. Estudos sugerem que a adição de um suspiro por minuto em pacientes com síndrome do desconforto respiratório agudo, ventilados em PSV, melhora a oxigenação e a mecânica pulmonar. OBJETIVO: Avaliar o impacto da manobra de recrutamento alveolar através de suspiro na mecânica pulmonar e oxigenação em pacientes ventilados mecanicamente, além de verificar o impacto hemodinâmico e a incidência de intercorrências associadas à utilização da técnica. MATERIAIS E MÉTODOS: Estudo experimental com 17 pacientes em ventilação mecânica, apresentando relação entre pressão parcial de oxigênio alveolar e fração inspirada de oxigênio (PaO2/FiO2) inferior a 300mmHg. Avaliou-se dados respiratórios, de mecânica pulmonar e hemodinâmicos. Os dados foram coletados durante três períodos: antes do suspiro, imediatamente após e 15 minutos depois da técnica. Dois suspiros por minuto foram administrados utilizando pressão em vias aéreas limitada em 40cmH2O, durante um tempo inspiratório de quatro segundos. RESULTADOS: Após o suspiro observou-se aumento da PaO2, pressão resistiva, complacência estática e relação PaO2/FiO2, além de diminuição da pressão de platô e pressão parcial de gás carbônico alveolar (PaCO2). Após 15 minutos da retirada do suspiro observou-se que a PaO2, pressão resistiva, complacência estática e relação PaO2/FiO2 mantiveram-se acima do valor basal, enquanto que a pressão de platô manteve-se abaixo. Não foi observada alteração significante nas variáveis hemodinâmicas. CONCLUSÃO: O suspiro em pacientes ventilados mecanicamente foi capaz de melhorar a oxigenação e a mecânica pulmonar, sem comprometer a estabilidade hemodinâmica.

In vitro and in vivo performance modelling and optimisation of different dry powder inhalers: A complementary study of neural networks, genetic algorithms and decision trees.

Aerosol delivery from DPIs could be affected by different factors. This study aimed to evaluate and predict the effects of different factors on drug delivery from DPIs. Modelling and optimisation for both in vitro and in vivo data of different DPIs (Diskus, Turbohaler and Aerolizer) were carried out using neural networks associated with genetic algorithms and the results are confirmed using a decision tree (DT) and random forest regressor (RFR). All variables (the type of DPI, inhalation flow, inhalation volume, number of inhalations and type of subject) were coded as numbers before using them in the modelling study. The analysis of the in vitro model showed that Turbohaler had the highest emitted dose compared with the Diskus and the Aerolizer. Increasing flow resulted in a gradual increase in the emitted dose. Little differences between the inhalation volumes 2 and 4 litres were shown at fast inhalation flow, and interestingly two inhalations showed somewhat higher emitted doses than one-inhalation mode with Turbohaler and Diskus at slow inhalation flow. Regarding the in vivo model, the percent of drug delivered to the lung was highly increased with Turbohaler and Diskus in healthy subjects where continuous contour lines were observed. The Turbohaler showed increased lung bioavailability with the two-inhalation modes, the Diskus showed a nearly constant level at both one and two inhalations at slow inhalation. The Turbohaler and Aerolizer showed little increasing effect moving from one to two inhalations at slow inhalation. Modelling of the input data showed a good differentiating and prediction power for both in vitro and in vivo models. The results of the modelling refer to the high efficacy of Diskus followed by Turbohaler for delivering aerosol. With two inhalations, the three DPIs showed an increase in the percent of drug excreted at slow inhalations.

The potential benefit of continuous metered-dose inhaler inhalation technique verbal counselling on asthmatic.

Subjects' improper usage of their metered-dose inhalers (MDI) is considered a chief cause of poor asthma control. The work presented here aims to evaluate the effect of MDI verbal counselling on subjects' lung function and inhalation technique. A total number of 900 asthmatic subjects (450 female) were gathered from University hospital outpatient clinics from January 2017 to May 2019 with a mean (SD) age 45.2 (17.1) years old. They were divided into two groups. The first was monthly asthma follow-up, for three visits, (450 (266 females) subjects). The other group was monthly asthma follow-up, for three visits plus MDI inhalation technique verbal counselling (450 (184 female) subjects). At the beginning of studying group 2 and at every monthly visit (three visits), each subject was asked to show the investigator his MDI inhalation technique and the number of mistakes was noticed and adjusted. Additionally, at each visit, their forced expiratory volume in one second (FEV1 ) as a percentage of the forced vital capacity (FVC) and peak expiratory flow (PEF) were measured. No subject dropped out from group 2; however, 95 subjects dropped out from group 1 with no improvement in the lung function tests. The mean number of accurate steps of the MDI inhalation technique observed in group 2 was improved significantly (P<.001) as the number of visits increased particularly in children. "Start to inhale slowly, through the mouth and at the same time press the canister to actuate a dose and maintain a slow and deep inhalation, through the mouth, until the lungs are full of air (This should take an adult 4-5seconds)" was the common repetitive mistake. There was a significant improvement (P<.05) in the lung function test scores after the counselling in group 2, especially in old subjects. MDI's counselling must be continually offered to the asthmatic subject at any possible chance to improve and sustain the optimal MDI inhalation technique and probably improve subjects' lung function score.

Tethered capsule en face optical coherence tomography for imaging Barrett’s oesophagus in unsedated patients

ObjectiveBarrett’s oesophagus (BE) screening outside the endoscopy suite can identify patients for surveillance and reduce mortality. Tethered capsule optical coherence tomography (OCT) can volumetrically image oesophageal mucosa in unsedated patients...

In silico optimization of targeted aerosol delivery in upper airways via Inhaled Volume Tracking

BackgroundDespite the widespread use of aerosol inhalation as a drug delivery method, targeted delivery to the upper airways remains an ongoing challenge in the quest for improved clinical response in respiratory disease. MethodsHere, we examine in silico flow and particle dynamics when using an oral Inhaled Volume Tracking manoeuvre. A short pulsed aerosol bolus is injected during slow inhalation flow rates followed by clean air, and a breath-hold is initiated once it reaches the desired depth. We explore the fate of a broad particle size range (1–40 μm) for both upright and supine positions. FindingsOur findings illustrate that despite attempts to mitigate dispersion using slower flow rates, the laryngeal jet disperses the aerosol bolus and thus remains a hurdle for efficient targeted delivery. Nevertheless, we show a decrease in extra-thoracic deposition; large aerosols in the range of 10–30 μm potentially outperform existing inhalation methods, showing deposition fractions of up to 80% in an upright orientation. InterpretationThe improved deposition during Inhaled Volume Tracking shows promise for clinical applications and could be leveraged to deliver larger payloads to the upper airways.

Effect of Inspiratory Maneuvers on Lung Deposition of Tobramycin Inhalation Powder: A Modeling Study.

Background: Tobramycin inhalation powder (TIP) and tobramycin inhalation solution (TIS) are considered equally effective for the treatment of chronic pulmonary Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients. The impact of TIP inhalation maneuvers on distribution of tobramycin is unknown. We hypothesized that (1) fast TIP inhalations result in greater extrathoracic and reduced small airway concentrations compared with slow or uninstructed TIP inhalations; (2) slow TIP inhalations result in greater small airway concentrations than TIS inhalations. The aim of the study was to assess TIP and TIS deposition with computational fluid dynamics (CFD). Methods: Uninstructed, instructed fast, and instructed slow TIP inhalations of CF patients on maintenance TIP therapy, and inhalations during nebulization of saline with PARI LC Plus® were recorded at home. Drug deposition was determined using TIP and TIS aerosol characteristics together with CFD simulations based on airway geometries from chest computed tomography scans. The drug concentration was assessed in extrathoracic, central, large, and small airways. Results: Twelve patients aged 12-45 years were included, and 144 CFD simulations were performed. In all individual analyses, the tobramycin concentrations were well above the threshold for effective dose of 10 times minimal inhibitory concentration throughout the bronchial tree. Extrathoracic concentrations were comparable between fast and uninstructed TIP inhalations, while slow inhalations resulted in reduced extrathoracic concentrations compared with uninstructed TIP inhalations (p = 0.024). Small airway concentrations were comparable between fast and uninstructed TIP inhalations, while slow TIP inhalations resulted in greater small airway concentrations than uninstructed TIP inhalations (p < 0.001). Small airway concentrations of TIS were comparable with those of slow TIP inhalations (p = 0.065), but greater than those of fast and uninstructed TIP inhalations (p < 0.001). Conclusion: All TIS and TIP inhalation maneuvers resulted in high enough concentrations, however, inhaling TIS or inhaling TIP slowly results in the greatest small airway deposition.

Asthmatic children and MDI verbal inhalation technique counseling

ObjectivesThe present work aimed to study the role of metered-dose inhalers (MDI) verbal counseling on asthmatic children patients inhalation technique and their pulmonary functions. MethodsIn this study many children younger than 18 years old with asthma were collected from University hospital outpatient clinics throughout two years period Their MDI inhalation technique was checked and the number of MDI inhalation technique mistakes were detected and corrected at the first visit and every month for two more visits (three visits). Their peak expiratory flow (PEF) and forced expiratory volume in 1 s (FEV1) as a percentage of the forced vital capacity (FVC) were checked at every visit. Results81 asthmatic subjects (54 female) younger than 18 years old were collected with a mean (SD) age 14.4 (1.8) years old. Most of the patients' owned MDI contained salbutamol, however, some patients were using Beclometasone MDI or Beclometasone and salbutamol combination MDI. The mean number of correct steps performed was significantly increased (p < 0.05) as the number of visits increased. “Place the MDI mouthpiece between the teeth and seal with lips” and “To maintain slow inhalation rate until lungs are full” were the least steps correctly performed by the asthmatics children studied. There was a significant increase (p < 0.05) in the pulmonary function test scores at the third visit. ConclusionsMDI's verbal counseling should be repeated and checked at every opportunity, especially with children, to improve and maintain the recommended MDI inhalation technique. That could be a tool to possibly improve patients' pulmonary functions.

Is "Slow Inhalation" Always Suitable for Pressurized Metered Dose Inhaler?

To achieve adequate inhalation therapy, a proper inhalation technique is needed in clinical practice. However, there is limited information on proper inhalation flow patterns of commercial inhalers. Here, we quantitatively estimated airway deposition of two commercial pressurized metered dose inhalers (pMDIs) to determine their optimal inhalation patterns. Sultanol® inhaler (drug particles suspended in a propellant, suspension-pMDI) and QVAR™ (drug dissolved in a propellant with ethanol, solution-pMDI) were used as model pMDIs. Aerodynamic properties of the two pMDIs were determined using an Andersen cascade impactor with human inhalation flow simulator developed by our laboratory. As indices of peripheral-airway drug deposition, fine particle fractions (FPFPA) at different inhalation flow rates were calculated. The time-dependent particle diameters of sprayed drug particles were determined by laser diffraction. On aerodynamic testing, FPFPA of suspension-pMDI significantly decreased depending on the increasing inhalation flow rate, while solution-pMDI achieved higher and constant FPFPA in the range of the tested inhalation flow rates. The particle diameter of solution-pMDI markedly decreased from 5 to 3μm in a time-dependent manner. Conversely, that of suspension-pMDI remained at 4μm during the spraying time. Although "slow inhalation" is recommended for pMDIs, airway drug deposition via solution-pMDI (extra-fine particles) is independent of patients' inhalation flow pattern. Clinical studies should be performed to validate instruction for use of pMDIs for each inhaler for the optimization of inhalation therapy.

Patient-specific modeling of aerosol delivery in healthy and asthmatic adults.

The magnitude and regional heterogeneity of airway obstructions in severe asthmatics is likely linked to insufficient drug delivery, as evidenced by the inability to mitigate exacerbations with inhaled aerosol medications. To understand the correlation between morphometric features, airflow distribution, and inhaled dosimetry, we perform dynamic computational simulations in two healthy and four asthmatic subjects. Models incorporate computed tomography-based and patient-specific central airway geometries and hyperpolarized 3He MRI-measured segmental ventilation defect percentages (SVDPs), implemented as resistance boundary conditions. Particles [diameters (dp) = 1, 3, and 5 μm] are simulated throughout inhalation, and we record their initial conditions, both spatially and temporally, with their fate in the lung. Predictions highlight that total central airway deposition is the same between the healthy subjects (26.6%, dp = 3 μm) but variable among the asthmatic subjects (ranging from 5.9% to 59.3%, dp = 3 μm). We found that by preferentially releasing the particles during times of fast or slow inhalation rates we enhance either central airway deposition percentages or peripheral particle delivery, respectively. These predictions highlight the potential to identify with simulations patients who may not receive adequate therapeutic dosages with inhaled aerosol medication and therefore identify patients who may benefit from alternative treatment strategies. Furthermore, by improving regional dose levels, we may be able to preferentially deliver drugs to the airways in need, reducing associated adverse side effects.NEW & NOTEWORTHY Although it is evident that exacerbation mitigation is unsuccessful in some asthmatics, it remains unclear whether or not these patients receive adequate dosages of inhaled therapeutics. By coupling MRI and computed tomography data with patient-specific computational models, our predictions highlight the large intersubject variability, specifically in severe asthma.

Inhaled salbutamol from aerolizer and diskus at different inhalation flows, inhalation volume and number of inhalations in both healthy subjects and COPD patients

The aim of the present study was to demonstrate the effect of inhalation-flow, inhalation-volume and number of inhalations on aerosol-delivery of inhaled-salbutamol from two different dry powder inhalers (DPIs) in both healthy-subjects and chronic obstructive pulmonary disease (COPD) patients. Relative pulmonary-bioavailability and systemic-bioavailability of inhaled-salbutamol, delivered by Diskus and Aerolizer, was determined in 24-COPD patients and 24-healthy subjects. The healthy-subjects and the COPD-patients participated in the study for 7 days in which they received 4 study doses of 200 μg salbutamol (one slow-inhalation, two slow-inhalations, one fast-inhalation, and two fast-inhalations) in four alternative days with 24 hr washout period after each dose. Two urine-samples were collected from each study subjects. The first was provided 30 min post inhalation (USAL0.5), as an index of relative pulmonary-bioavailability, and the second was pooled to 24 hr post inhalation (USAL24), as an index of systemic-bioavailability. Fast-inhalation resulted in significantly higher USAL0.5 and USAL24 than slow-inhalation (p < 0.05) after one-inhalation in both healthy-subjects and COPD-patients but there was no significant difference between slow and fast-inhalation after two-inhalations. One-inhalation resulted in significantly higher USAL0.5 and USAL24 in healthy-subjects compared to COPD-patient at both slow and fast-inhalation (p < 0.05) except USAL0.5 with Diskus at slow-inhalation there was no significant difference. Also, two-inhalations resulted in significantly higher USAL0.5 and USAL24 compared to one-inhalation at slow-inhalation only (p < 0.05). No significant difference was found between Aerolizer and Diskus except in USAL0.5 of one slow-inhalation in both health-subjects and COPD-patients (p = 0.048 and 0.047, respectively). Device-formula relation is present at low inhalation-flow since Diskus resulted in significantly higher USAL0.5 and USAL24 in healthy-subjects compared to COPD-patient at slow inhalation than Aerolizer. It is essential to inhale-twice and as hard and deep as possible from each dose when using DPI especially with COPD-patients having poor inspiratory efforts such as elderly patients and children.

TheImpact of Addinga Training Device to Familiar Counselling on Inhalation Technique and Pulmonary Function of Asthmatics.

We have investigated the effect of adding a pressurized metered dose inhaler (pMDI) training device to verbal counselling on pulmonary function and inhalation technique. A total of 304 adult asthmatic subjects (> 18years old) were enrolled in a 3-month study of assessment and education. They were divided into an investigation group (Trainhaler plus Flo-Tone and verbal counselling, n = 261, mean age 49.2years) and a control group (verbal counselling only, n = 43, mean age 48.7years). Pulmonary function and inhalation technique were evaluated, mistakes noted, and the correct technique advised at three consecutive monthly visits. Visits also included verbal pMDI counselling (both groups) and training device coaching (investigation group). By visit2, the mean number of technique errors decreased significantly (p < 0.05) in both groups (investigation group p < 0.001). The investigation group demonstrated a marked decrease in the frequency of the critical error of maintaining a slow inhalation rate until the lungs are full-a technique difficult to learn via verbal counselling alone. The improvement in pulmonary function was significant from the second clinic visit in the investigation group (p < 0.05) and from the third visit in both groups (p < 0.001). Use of a training device combined with verbal counselling improved inhalation technique. An earlier, significant improvement was also noted in pulmonary function.

3D phase contrast MRI in models of human airways: Validation of computational fluid dynamics simulations of steady inspiratory flow.

Knowledge of airflow patterns in the large airways is of interest in obstructive airways disease and in the development of inhaled therapies. Computational fluid dynamics (CFD) simulations are used to study airflow in realistic airway models but usually need experimental validation. To develop MRI-based methods to study airway flow in realistic 3D-printed models. Case control. Two 3D-printed lung models. 1.5-3T, flow MRI. Two human airway models, respectively including and excluding the oral cavity and upper airways derived from MR and CT imaging, were 3D-printed. 3D flow MRI was performed at different flow conditions corresponding to slow and steady airflow inhalation rates. Water was used as the working fluid to mimic airflow. Dynamic acquisition of 1D velocity profiles was also performed at different locations in the trachea to observe variability during nonsteady conditions. Linear regression analysis to compare both flow velocity fields and local flow rates from CFD simulations and experimental measurement with flow MRI. A good agreement was obtained between 3D velocity maps measured with flow MRI and predicted by CFD simulations, with linear regression R-squared values ranging from 0.39 to 0.94 when performing a pixel-by-pixel comparison of each velocity component. The flow distribution inside the lung models was also similar, with average slope and R-squared values of 0.96 and 0.99, respectively, when comparing local flow rates assessed at different branching locations. In the model including the upper airways, a turbulent laryngeal jet flow was observed with both methods and affected remarkably the velocity profiles in the trachea. We propose flow MRI using water as a surrogate fluid to air, as a validation tool for CFD simulations of airflow in geometrically realistic models of the human airways. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1400-1409.

Factors DeterminingIn VitroLung Deposition of Albuterol Aerosol Delivered by Ventolin Metered-Dose Inhaler

The effectiveness of metered-dose inhalers (MDIs) in delivering medication to the lungs highly depends on its correct usage technique. Current guidelines state optimal technique for high lung deposition should include a slow inhalation (>5 seconds) at an inspiratory flow rate of 30 L/min and inhaler actuation at the start of inhalation. However, these recommendations were based on clinical studies using CFC (chlorofluorocarbon)-MDIs and in vitro studies of HFA (hydrofluoroalkane)-MDIs using idealized MDI techniques of uniform inhalation and actuation, disregarding the nonuniform techniques of actual patients. To better understand the effects of time-varying MDI usage parameters on lung deposition of aerosol delivered by an HFA-MDI, we conducted an in vitro study modeled on real-life variable inspiratory flow and actuation techniques recorded from 15 subjects with asthma/chronic obstructive pulmonary disease (COPD). We developed a model representing the time-varying inspiratory flow waveforms and actuation timings based on 43 MDI techniques recorded from patients. Furthermore, we constructed an in vitro experimental setup using a mouth-throat cast, programmable MDI actuator, and breath simulator to evaluate lung deposition for the MDI techniques derived from our model. High inspiratory flow rates, 60-90 L/min, consistently resulted in high in vitro lung deposition (>40%) of aerosol (albuterol delivered from Ventolin HFA-MDI) compared to 30 L/min when MDI actuation occurred in the first half of inhalation. Also, positive coordination resulted in higher in vitro lung deposition compared with negative or zero coordination (actuating before or at the start of inspiration). Furthermore, variation in coordination affected lung deposition more significantly (23%) than flow rate or duration of inspiration (≤5%). In an in vitro experimental model based on inhalation data from patients with asthma and COPD, we demonstrated that aerosol lung deposition emitted from Ventolin HFA-MDI is most optimal for MDI actuation in the first half of inspiration at high flow rates (60-90 L/min).