Inhalation Maneuver Research Articles

Flow Profiles Identify Sources of Poor Metered Dose Inhaler Technique: An observational study in long-term pMDI users

BackgroundInhaled medications are commonly used as therapy for obstructive lung disease (OLD) yet poor technique from pressurized metered dose inhalers (pMDI) can severely limit drug delivery and therapeutic efficacy. A novel flow sensor has been developed to characterize inhalation flow profiles from pMDIs. Research QuestionAmong OLD subjects, flow profiles during pMDI inhalation maneuvers would expose poor patterns of pMDI use, which can be used to remediate pMDI technique. Study Design and MethodsA novel flow sensor was coupled to a placebo pMDI inhaler to characterize inhalation technique in 70 OLD participants from a pulmonary clinic. pMDI inhalation flow profiles generated actuation timing, mean inspiratory airflow (MIF) and inspired volume before and after visualizing these features. McNemar’s was used to characterize the impact of training on pMDI inhalation metrics. The post-actuation inspired volume was normalized to inspiratory capacity (IC). ResultsAmong participants with 17.4 (SD = 17.9) years of pMDI use, flow profiles uncovered mistimed actuations in 47.1% and poor inspiratory flow rates in 30.0% of subjects. After visualizing flow profiles, participants improved actuation timing (c2(1) =12.042, p < .001), mean inhaled volume (87.9 to 105.6% of IC, p<0.001) and the combined inhalation metrics (c2(1) =8.45, p = 0.003). InterpretationFlow profiles helped uncover and remediate specific defects in pMDI technique in the majority of chronic OLD users. Flow profiles from inhaled medications can be used to enhance drug delivery to the lung.

Dry powder inhaler design and particle technology in enhancing Pulmonary drug deposition: challenges and future strategies.

The efficient delivery of drugs from dry powder inhaler (DPI) formulations is associated with the complex interaction between the device design, drug formulations, and patient's inspiratory forces. Several challenges such as limited emitted dose of drugs from the formulation, low and variable deposition of drugs into the deep lungs, are to be resolved for obtaining the efficiency in drug delivery from DPI formulations. The objective of this study is to review the current challenges of inhaled drug delivery technology and find a way to enhance the efficiency of drug delivery from DPIs. Using appropriate keywords and phrases as search terms, evidence was collected from the published articles following SciFinder, Web of Science, PubMed and Google Scholar databases. Successful lung drug delivery from DPIs is very challenging due to the complex anatomy of the lungs and requires an integrated strategy for particle technology, formulation design, device design, and patient inhalation force. New DPIs are still being developed with limited performance and future device design employs computer simulation and engineering technology to overcome the ongoing challenges. Many issues of drug formulation challenges and particle technology are concerning factors associated with drug dispersion from the DPIs into deep lungs. This review article addressed the appropriate design of DPI devices and drug formulations aligned with the patient's inhalation maneuver for efficient delivery of drugs from DPI formulations.

Optimal Inhalation Profile of Pressurized Metered Dry Powder Inhaler Using a Valved Holding Chamber: A Dynamic Analysis.

Background: The combined use of a pressurized metered-dose inhaler and valved holding chamber (pMDI+VHC) is recommended to improve efficiency and safety; however, aerosol release is likely to vary with the inhalation maneuver. This in vitro study investigated the aerodynamic characteristics and aerosol release features of pMDI+VHC (Aerochamber, Trudell Medical International). Methods: The static and dynamic changes in the airway resistance (Raw) during inhalation (withdrawal) through pMDI+VHC were measured. Subsequently, the aerosol released from pMDI+VHC was measured using simplified laser photometry during withdrawal with either fast ramp-up then steady or slow ramp-up followed by gradual decrement at different intensities and times to peak flow (TPWF). Results: Raw increased linearly with changes in the withdrawal flow (WF) rate between 10 and 50 L/min. The slope was steep in the low WF range (<50 L/min) and became milder in the higher range. The aerosol mass tended to increase with an increase in the peak WF (PWF) of slow ramp-up profile. When three different WF increment slopes (TPWF: 0.4, 1.4, and 2.4 seconds) were compared, the released aerosol mass tended to decrease, and the aerosol release time was prolonged at longer TPWF. When the PWF was increased, the aerosol release time became shorter, and the withdrawn volume required for 95% aerosol release became larger; however, it did not exceed 0.4 L at suitable TPWF (0.4 seconds). Conclusion: Raw analysis suggests that inhalation at 30-50 L/min is suitable for pMDI+VHC in this setting. Rapid (TPWF, 0.4 seconds) inhalation, but not necessarily long (maximum 2.0 seconds) and deep (but larger than 0.55 L), is also recommended. Practically, direct inhalation to be weaker than usual breathing, as fast as possible, and far less than 2.0 seconds.

Dry Powder Inhalers: From Bench to Bedside.

Dry powder inhalers (DPIs) are now widely prescribed and preferred by the majority of patients. These devices have many advantages over the traditional pressurized metered-dose inhaler (pMDI) but they do have disadvantages. The characteristics of the dose emitted from a DPI are affected by the inhalation manoeuvre used by a patient. Each patient is different and the severity of their lung disease varies from mild to very severe. This affects how they use an inhaler and so determines the type of dose they inhale. An understanding of the pharmaceutical science related to DPIs is important to appreciate the relevance of how patients inhale through these devices. Also, each type of DPI has its unique dose preparation routine, and thus it is essential to follow these recommended steps because errors at this stage may result in no dose being inhaled. All issues related to the inhalation manoeuvre and dose preparation are addressed in this chapter. The importance of the inhalation technique is highlighted with a realization of inhale technique training and checking. During routine patient management, devices should not be switched nor doses increased unless the patient has demonstrated that they can and do use their DPI.

Identifying critical inhalation technique errors in Dry Powder Inhaler use in patients with COPD based on the association with health status and exacerbations: findings from the multi-country cross-sectional observational PIFotal study

BackgroundCorrect inhaler use depends on a complex interplay of factors, including device preparation and generating sufficient inspiratory flow. It is currently unknown which inhalation technique errors can be considered critical in Chronic Obstructive Pulmonary Disease (COPD) patients on Dry Powder Inhaler (DPI) maintenance therapy.ObjectiveTo investigate the association between inhalation technique errors and health status or exacerbations in patients with COPD. Additionally, the association between the number of errors and COPD outcomes was determined.MethodsThe PIFotal study is a cross-sectional multi-country observational study in a primary care setting, including 1434 COPD patients aged ≥ 40 years (50.1% female; mean age 69.2 yrs) using a DPI for their maintenance therapy. Inhalation technique was video recorded and scored by two independent researchers using inhaler-specific checklists. Health status was assessed with two questionnaires; the Clinical COPD Questionnaire (CCQ) and the COPD Assessment Test (CAT). The number of moderate and severe exacerbations in the past 12 months was recorded. Critical errors were identified based on their association with health status or exacerbations through multi-level prediction models adjusted for identified confounding.ResultsErrors in inhalation technique steps ‘Breathe in’, ‘Hold breath’, and ‘Breathe out calmly after inhalation’ were significantly associated with poorer CCQ and CAT outcomes and thus deemed critical. None of the errors were significantly associated with moderate exacerbations. Patients with errors ‘Preparation’, ‘Hold inhaler in correct position during inhalation’, and ‘Breathe in’ had significantly more severe exacerbations, and therefore these errors were also deemed critical. 81.3% of patients with COPD made at least one critical error. Specific combinations of errors were associated with worse outcomes. The more inhalation technique errors identified, the poorer the health status and the higher the exacerbation rate.ConclusionIn this study, we identified multiple critical inhalation technique errors in COPD patients using DPIs each associated with poorer outcomes. Explorative analysis revealed that specific combinations of errors may be of clinical relevance, especially those related to the inhalation manoeuvre. COPD outcomes worsened with increasing error count. These results warrant further prospective longitudinal studies to establish the effect of correcting these errors on COPD control.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04532853 (31/08/2020)

The effect of lung emptying before the inhalation of aerosol drugs on drug deposition in the respiratory system

The amount of drug depositing in the airways depends, among others, on the inhalation manoeuvre and breathing parameters. The objective of this study was to quantify the effect of lung emptying before the inhalation of drugs on the lung doses. Thirty healthy adults were recruited. Their breathing profiles were recorded while inhaling through six different emptied DPI devices without breathe-out and after comfortable or forced exhalation. The corresponding emitted doses and aerosol size distributions were derived from the literature. The Stochastic Lung Model was used to estimate the deposited doses. In general, forceful exhalation caused increased flow rate and inhaled air volume. Increased flow rate led to the increase of the average lung dose for drugs with positive lung dose-flow rate correlation (e.g. Symbicort®: relative increase of 6.7%, Bufomix®: relative increase of 9.2%). For drugs with negative correlation of lung dose with flow rate (all the studied drugs except the above two) lung emptying caused increased (Foster® by 2.7%), almost unchanged (Seebri®, Relvar®, Bretaris®) and also decreased (Onbrez® by 6.6%) average lung dose. It is worth noting that there were significant inter-individual differences, and lung dose of each drug could be increased by a number of subjects. In conclusion, the change of lung dose depends on the degree of lung emptying, but it is also inhaler and drug specific. Forceful exhalation can help in increasing the lung dose only if the above specificities are taken into account.

Modeling of pulmonary deposition of agents of open and fixed dose triple combination therapies through two different low-resistance inhalers in COPD: a pilot study.

Inhalation therapy is a cornerstone of treating patients with chronic obstructive pulmonary disease (COPD). Inhaler devices might influence the effectiveness of inhalation therapy. We aimed to model and compare the deposition of acting agents of an open and a fixed dose combination (FDC) triple therapy and examine their repeatability. We recruited control subjects (Controls, n = 17) and patients with stable COPD (S-COPD, n = 13) and those during an acute exacerbation (AE-COPD, n = 12). Standard spirometry was followed by through-device inhalation maneuvers using a pressurized metered dose inhaler (pMDI) and a soft mist inhaler (SMI) to calculate deposition of fixed dose and open triple combination therapies by numerical modeling. Through-device inspiratory vital capacity (IVCd) and peak inspiratory flow (PIFd), as well as inhalation time (tin) and breath hold time (tbh) were used to calculate pulmonary (PD) and extrathoracic deposition (ETD) values. Deposition was calculated from two different inhalation maneuvers. There was no difference in forced expiratory volume in 1 s (FEV1) between patients (S-COPD: 42 ± 5% vs. AE-COPD: 35 ± 5% predicted). Spiriva® Respimat® showed significantly higher PD and lower ETD values in all COPD patients and Controls compared with the two pMDIs. For Foster® pMDI and Trimbow® pMDI similar PD were observed in Controls, while ETD between Controls and AE-COPD patients did significantly differ. There was no difference between COPD groups regarding the repeatability of calculated deposition values. Ranking the different inhalers by differences between the two deposition values calculated from separate maneuvers, Respimat® produced the smallest inter-measurement differences for PD. Our study is the first to model and compare PD using pMDIs and an SMI as triple combination in COPD. In conclusion, switching from FDC to open triple therapy in cases when adherence to devices is maintanined may contribute to better therapeutic effectiveness in individual cases using low resistance inhalers.

A Novel Trans-Tracheostomal Retrograde Inhalation Technique Increases Subglottic Drug Deposition Compared to Traditional Trans-Oral Inhalation.

Subglottic stenosis represents a challenging clinical condition in otolaryngology. Although patients often experience improvement following endoscopic surgery, recurrence rates remain high. Pursuing measures to maintain surgical results and prevent recurrence is thus necessary. Steroids therapy is considered effective in preventing restenosis. Currently, however, the ability of trans-oral steroid inhalation to reach and affect the stenotic subglottic area in a tracheotomized patient is largely negligible. In the present study, we describe a novel trans-tracheostomal retrograde inhalation technique to increase corticosteroid deposition in the subglottic area. We detail our preliminary clinical outcomes in four patients treated with trans-tracheostomal corticosteroid inhalation via a metered dose inhaler (MDI) following surgery. Concurrently, we leverage computational fluid-particle dynamics (CFPD) simulations in an extra-thoracic 3D airway model to gain insight on possible advantages of such a technique over traditional trans-oral inhalation in augmenting aerosol deposition in the stenotic subglottic region. Our numerical simulations show that for an arbitrary inhaled dose (aerosols spanning 1-12 µm), the deposition (mass) fraction in the subglottis is over 30 times higher in the retrograde trans-tracheostomal technique compared to the trans-oral inhalation technique (3.63% vs. 0.11%). Importantly, while a major portion of inhaled aerosols (66.43%) in the trans-oral inhalation maneuver are transported distally past the trachea, the vast majority of aerosols (85.10%) exit through the mouth during trans-tracheostomal inhalation, thereby avoiding undesired deposition in the broader lungs. Overall, the proposed trans-tracheostomal retrograde inhalation technique increases aerosol deposition rates in the subglottis with minor lower-airway deposition compared to the trans-oral inhalation technique. This novel technique could play an important role in preventing restenosis of the subglottis.

Misuse of Respiratory Inhalers Among Hospitalized Patients in a Tertiary Health Care Hospital in Kabul.

Evaluation of the techniques of respiratory inhaler use among stable inpatients with COPD in Ali Abad Teaching Hospital. This cross-sectional study was conducted between April 2020 and October 2022 at the cardiopulmonary department of Ali-Abad Teaching Hospital. Participants were requested to demonstrate how to use their prescribed inhalation devices. The inhaler's accuracy was evaluated using checklists that had been previously established and included key procedures. We studied 318 patients performing a total of 398 inhalation maneuvers with five different IDs. Across all studied inhalation maneuvers, the maximum number of misuses was observed in those using the Respimat (97.7%), and the minimum number of misuses was observed in those using the Accuhaler (58.8%). For the pMDI, the steps "take a deep breath after activating the inhaler" and "hold the breath a few seconds" were most frequently inaccurately performed. Regarding the pMDI with spacer, the steps "exhale fully" were most commonly carried out in mistake. For the Respimat, the steps "hold the breath a few seconds after inhalation activation" and "exhale fully" were most frequently inaccurately performed. According to gender, the misuse was less in females for all studied inhalers (p<0.05). Higher proportion of literate participant correctly used all types of inhalers as compared to the illiterate patients (p<0.05). According to the findings of this study, the majority of patients (77.6%) lacked knowledge of proper inhaler technique. The misuse rates were high for all studied inhalers; however, among studied inhalers, the Accuhaler had the greatest proportion of correct inhalation techniques. In order to ensure proper inhaler technique, patients should be educated before receiving inhaler medicines. Therefore, it is crucial for doctors, nurses, and other healthcare professionals to comprehend the problems with the performance and proper usage of these inhaler devices.

Clinical recommendations for dry powder inhaler use in the management of COPD in primary care

Over 1400 patients using dry powder inhalers (DPIs) to deliver COPD maintenance therapies were recruited across Europe and Australia. Their peak inspiratory flow (PIF) was measured, inhaler technique was observed, and adherence to treatment assessed. From relating the findings with patient health status, and thereby identifying critical errors, key clinical recommendations for primary care clinicians were determined, namely – measure PIF before prescribing a DPI to ensure inhalation manoeuvre ability is well-matched with the device. Some patients could benefit from inhalation training whereas others should have their DPI changed for one better suited to their inspiratory ability or alternatively be prescribed an active device (such as a soft mist inhaler or pressurized metered dose inhaler). Observing the inhalation technique was valuable however this misses suboptimal PIF (approaching one fourth of patients with a satisfactory observed manoeuvre had a suboptimal PIF for their DPI). Assess adherence as deliberate non-adherence can point to a mismatch between a patient and their inhaler (deliberate non-adherence was significantly associated with PIFs below the minimum for the DPI). In-person observation of inhalation technique was found to be inferior to video rating based on device-specific checklists. Where video assessments are not possible, observation training for healthcare professionals would therefore be valuable particularly to improve the ability to identify the critical errors associated with health status namely ‘teeth and lips sealed around mouthpiece’, ‘breathe in’ and ‘breathing out calmly after inhalation’. However, it is recommended that observation alone should not replace PIF measurement in the DPI selection process.Trial registration:https://clinicaltrials.gov/ct2/show/NCT04532853.

Correct treatment regimen and inhalation technique are the components of success in bronchial asthma in the era of COVID-19

The goal of Asthma treatment is to achieve a controlled condition, that is, to minimize the burden of symptoms and the risk of exacerbations. Many factors hinder the achievement of this goal: non-compliance with recommendations for drug therapy, the influence of concomitant diseases, the impact of triggers, low patient adherence to prescribed treatment, violation of inhalation technique. In general, there is no significant difference in the risk of hospitalization or mortality due to COVID-19 in patients with Asthma. At the same time, studies show that non-allergic Asthma, severe Asthma, Asthma in combination with obesity, lack of adequate basic therapy can create the greatest risk of infection and severe clinical outcomes of COVID-19. Asthma can be a predictor of a prolonged intubation period in severe respiratory failure during COVID-19, especially in people younger than 65 years. GINA experts agree that during a pandemic, it is especially important that patients with Asthma continue taking basic therapy, including inhaled corticosteroids (ICS), as prescribed by the recommendations. ICS therapy in combination with long-acting β2-agonists (LABA) is the main pharmacological method of treating moderate and severe Asthma in adolescents and adults. A single inhaler regimen with the use of a combination of ICS/formoterol is associated with a lower risk of severe exacerbations compared with supportive treatment of ICS/LABA in combination with SABA on demand. Studies show that the technique of inhalation maneuver can significantly affect the success of therapy. A wide variety of DPI causes problems with the choice and use by patients.

Suboptimal Peak Inspiratory Flow and Critical Inhalation Errors are Associated with Higher COPD-Related Healthcare Costs.

PurposeTo assess the relationship between suboptimal Peak Inspiratory Flow (sPIF), inhalation technique errors, and non-adherence, with Healthcare Resource Utilisation (HCRU) in Chronic Obstructive Pulmonary Disease (COPD) patients receiving maintenance therapy via a Dry Powder Inhaler (DPI).Patients and methodsThe cross-sectional, multi-country PIFotal study included 1434 COPD patients (≥40 years) using a DPI for maintenance therapy. PIF was measured with the In-Check DIAL G16, and sPIF was defined as a typical PIF lower than required for the device. Inhalation technique was assessed by standardised evaluation of video recordings and grouped into 10 steps. Patients completed the “Test of Adherence to Inhalers” questionnaire. HCRU was operationalised as COPD-related costs for primary healthcare, secondary healthcare, medication, and total COPD-related costs in a 1-year period.ResultsParticipants with sPIF had higher medication costs compared with those with optimal PIF (cost ratio [CR]: 1.07, 95% CI [1.01, 1.14]). Multiple inhalation technique errors were associated with increased HCRU. Specifically, “insufficient inspiratory effort” with higher secondary healthcare costs (CR: 2.20, 95% CI [1.37, 3.54]) and higher total COPD-related costs (CR: 1.16, 95% CI 1.03–1.31). “no breath-hold following the inhalation manoeuvre (<6 s)” with higher medication costs (CR: 1.08, 95% CI [1.02, 1.15]) and total COPD-related costs (CR 1.17, 95% CI [1.07, 1.28]), and “not breathing out calmly after inhalation” with higher medication costs (CR: 1.19, 95% CI [1.04, 1.37]). Non-adherence was not significantly associated with HCRU.ConclusionsPIF and inhalation technique errors were associated with higher COPD-related healthcare utilisation and costs in COPD patients on DPI maintenance therapy.

In Vitro Estimation of Tracheobronchial and Alveolar Doses Using Filters

To date, in vitro estimation of doses delivered by an inhaler to the different major regions of the lung has required combining particle size measurements of the inhaled aerosol with in silico deposition models. Such a two step process is labor and time intensive. Here, we describe instead the development of an apparatus that allows direct estimation of regional lung deposition by measurement of doses collected on purpose-built metal grid filters that mimic tracheobronchial deposition efficiency. Placing these filters downstream of the Alberta Idealized Throat and upstream of a final filter allows collection of doses depositing in the extrathoracic, tracheobronchial and alveolar regions. Artificial electrostatic deposition on the metal tracheobronchial filters is prevented by a custom inline electrostatic neutralizer. We use the resulting apparatus to estimate regional deposition with a variety of dry powder inhalers during realistic, time-varying inhalation maneuvers and three pMDIs with a constant flow rate of 30 l/min. These results are compared to those obtained with the traditional two step approach that combines cascade impaction with a regional deposition model. Good agreement is found between the two approaches, indicating that the present direct method may be an efficient, time-saving alternative method for in vitro estimation of regional lung doses.

Measuring Peak Inspiratory Flow in Patients with Chronic Obstructive Pulmonary Disease.

Dry powder inhalers (DPIs) are breath actuated, and patients using DPIs need to generate an optimal inspiratory flow during the inhalation maneuver for effective drug delivery to the lungs. However, practical and standardized recommendations for measuring peak inspiratory flow (PIF)—a potential indicator for effective DPI use in chronic obstructive pulmonary disease (COPD)—are lacking. To evaluate recommended PIF assessment approaches, we reviewed the Instructions for Use of the In-Check™ DIAL and the prescribing information for eight DPIs approved for use in the treatment of COPD in the United States. To evaluate applied PIF assessment approaches, we conducted a PubMed search from inception to August 31, 2021, for reports of clinical and real-life studies where PIF was measured using the In-Check™ DIAL or through a DPI in patients with COPD. Evaluation of collective sources, including 47 applicable studies, showed that instructions related to the positioning of the patient with their DPI, instructions for exhalation before the inhalation maneuver, the inhalation maneuver itself, and post-inhalation breath-hold times varied, and in many instances, appeared vague and/or incomplete. We observed considerable variation in how PIF was measured in clinical and real-life studies, underscoring the need for a standardized method of PIF measurement. Standardization of technique will facilitate comparisons among studies. Based on these findings and our clinical and research experience, we propose specific recommendations for PIF measurement to standardize the process and better ensure accurate and reliable PIF values in clinical trials and in daily clinical practice.

Evaluating the technique of using MDI and DPI in patients with respiratory disease

Inhalation therapy plays a major role in treatment of respiratory diseases. Correct inhalation technique is crucial for effective clinical outcomes.The aim of this study was to evaluate and analyse technique of use of Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) in patients with respiratory disease.This observational study was conducted at pulmonary outpatient department of a tertiary care hospital.30 patients were enrolled using convenience sampling. Participants’ demographic and disease specific data was recorded. Participants were asked to use their inhaler just as they would at home. The technique of device use was observed and recorded using inhaler specific checklists. Data collected was analyzed using descriptive statistics.Out of 30 patients 26 were using MDI, 23 of which (92%) performed at least 1 error. Among 4 patients using DPI, 3 (75%) performed at least 1 error. Patients using MDI for more than 1 year performed less errors compared to those who had been using MDI for less than 1 year, however the difference observed was not significant (n=26, p= 0.304). 29 patients (96%) received education about inhaler device use. The most common incorrectly performed steps were “complete exhalation” and “breath hold.”92% of MDI and 75% of DPI users made at least one error during the inhalation maneuver despite majority being educated about inhaler technique. The most frequently performed incorrect steps for MDI and DPI were “Complete exhalation” and “Breath hold”.

AN INVESTIGATION OF FACTORS AFFECTING INHALATION PROFILES OF PATIENTS WITH COPD

TOPIC: Obstructive Lung Diseases TYPE: Original Investigations PURPOSE: Inhaled therapies are the cornerstone of treatment for COPD. In order to achieve an optimal therapeutic response, a patient must be adherent to treatment and able to use their inhaler appropriately. Spirometry can be used to assess a patient’s potential inspiratory ability; however, such assessments may not predict inhaler performance in routine use. This study assessed how inhalation profiles vary between spontaneous (inspiration during uncoached and normal inhaler use) and maximal (forceful and deep inhalation from the device) maneuvers and with varying inhaler inspiratory resistance (IR) in patients with moderate-to-very-severe COPD. METHODS: In this randomized, double-blind (with respect to IR) three-period crossover study, COPD patients with a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ≤0.7, no exacerbation in the last 6 weeks, and no previous experience with the inhaler under study were randomized to treatment with a placebo soft mist inhaler of low, medium and high IR. Following each 7-day treatment period (each period with an inhaler of different IR), each patient’s inhalation profile was assessed 30 minutes post-albuterol through the inhaler connected to a Viasys MasterScope (following ATS guidelines for spirometry). Both spontaneous and maximal inhalation profiles were recorded and described in terms of peak inspiratory flow (PIF), total inhalation time (Tin), total inhaled volume (VCin), time to PIF (TPIF), elapsed time over which a flow of >80% of peak flow was achieved (ET80%), and inhaled volume at PIF as a percentage of VCin (VPIF). Patients were assigned to one of three cohorts based on their baseline post-bronchodilator %predicted FEV1 (<30%, very severe; 30%–<50%, severe; 50%–<80%, moderate). RESULTS: Thirty-four patients completed the study (COPD severity: 10 very severe, 12 severe, 12 moderate; 76.5% male; mean age, 65yrs; mean pack-yrs, 47.8; mean time since diagnosis, 145.6 months). With increasing disease severity, PIF and VCin reduced and ET80% tended to increase (the inhalation profiles became smaller, with a lower and broader peak). Increasing inhaler flow resistance caused PIF, VCin and VPIF to decrease and Tin, TPIF and ET80% to increase (inhalation profiles were smaller, with a lower and broader peak). With maneuver coaching, PIF and VCin increased, while Tin, TPIF, ET80% were reduced (inhalation profiles were larger, with a higher and narrower peak). CONCLUSIONS: Real-world inhalation profiles vary dependent upon COPD disease severity, type of inhalation maneuver (spontaneous or maximal) and internal inhaler resistance. CLINICAL IMPLICATIONS: Inhaler therapy requires training, and inhalers that operate independently of the user’s inhalation profile could be expected to be more robust in routine use. Spirometry assessments (maximal maneuver at low resistance) may not predict a patient’s routine inhalation performance. DISCLOSURES: No relevant relationships by Branko Jugovic, source=Web Response Consultant relationship with AstraZeneca Please note: $20001 - $100000 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with Chiesi Please note: $20001 - $100000 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with Novartis Please note: $1001 - $5000 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with Boehinger Please note: $5001 - $20000 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with GSK Please note: $5001 - $20000 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with Menaini Please note: $5001 - $20000 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with Therevance Please note: $1001 - $5000 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with Cipla Please note: $1001 - $5000 by Dave Singh, source=Web Response, value=Consulting fee Consultant relationship with Glenmark Please note: now Added 04/29/2021 by Dave Singh, source=Web Response, value=Consulting fee Employee relationship with Boehringer Ingelheim International GmbH Please note: 1998-present Added 04/29/2021 by Herbert Wachtel, source=Web Response, value=Salary

Impact of PIF, Inhalation Technique and Medication Adherence on Health Status and Exacerbations in COPD: Protocol of a Real-World Observational Study (PIFotal COPD Study).

IntroductionDry powder inhalers (DPIs), a commonly prescribed inhaler type for respiratory diseases, require patients to generate sufficient peak inspiratory flow (PIF) to ensure optimal drug delivery to the airways. Effectiveness of therapy also requires a good inhalation technique and adequate medication adherence. For patients with chronic obstructive pulmonary disease (COPD), recent studies conducted in tertiary care suggest that DPI users with suboptimal PIF have poorer COPD-related health status and increased exacerbation risk versus those with optimal PIF. The PIFotal study will investigate the impact of PIF, inhalation technique and medication adherence on patient-reported outcomes in patients with COPD in primary care using a DPI for their maintenance therapy.Methods and AnalysisThis cross-sectional observational study will assess 1200 patients (aged ≥ 40 years, diagnosed with COPD and using a DPI for COPD maintenance therapy for ≥ 3 months) from the Netherlands, Spain, Portugal, Poland, Greece and Australia. Assessments will consist of (1) PIF measurements (usual patient inhalation manoeuvre, maximal PIF against resistance of own inhaler, and maximal PIF against low resistance); (2) Clinical COPD Questionnaire (CCQ), COPD Assessment Test and Test of Adherence to Inhalers scores; and (3) video recordings of patient inhalation technique. Dependent variables include health status (CCQ score), number of self-reported exacerbations in previous 12 months, and healthcare resource utilisation in previous 6 months. Independent variables include PIF values, inhalation technique errors, medication adherence, and demographic and clinical characteristics. In the primary analysis, the mean difference in CCQ score between patients (1) with optimal/suboptimal PIF, (2) exhibiting/not exhibiting inhalation technique errors, and (3) adhering/not adhering to medication will be examined in a multivariable linear mixed model.EthicsThe study protocol was approved by ethics committees/institutional review boards of all participating sites prior to enrolment; written informed consent was obtained from all study participants.Trial Registration NumberClinicalTrials.gov: NCT04532853.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41030-021-00172-7.

Flow and Particle Modelling of Dry Powder Inhalers: Methodologies, Recent Development and Emerging Applications.

Dry powder inhaler (DPI) is a device used to deliver a drug in dry powder form to the lungs. A wide range of DPI products is currently available, with the choice of DPI device largely depending on the dose, dosing frequency and powder properties of formulations. Computational fluid dynamics (CFD), together with various particle motion modelling tools, such as discrete particle methods (DPM) and discrete element methods (DEM), have been increasingly used to optimise DPI design by revealing the details of flow patterns, particle trajectories, de-agglomerations and depositions within the device and the delivery paths. This review article focuses on the development of the modelling methodologies of flow and particle behaviours in DPI devices and their applications to device design in several emerging fields. Various modelling methods, including the most recent multi-scale approaches, are covered and the latest simulation studies of different devices are summarised and critically assessed. The potential and effectiveness of the modelling tools in optimising designs of emerging DPI devices are specifically discussed, such as those with the features of high-dose, pediatric patient compatibility and independency of patients’ inhalation manoeuvres. Lastly, we summarise the challenges that remain to be addressed in DPI-related fluid and particle modelling and provide our thoughts on future research direction in this field.

Patient Inspiratory Maneuver Performance; Peak Lungpower, Acceleration and Volume.

Background: Use of drug delivery devices between nebulizers, dry powder inhalers (DPIs), or metered dose inhalers (MDIs), for treating patients with asthma and chronic obstructive pulmonary disease (COPD), is based on patients' capability of coordinating the inhalation maneuver and achieving sufficient airflow. There are limited data available with regard to how patients meet the requirements of successful inhalation performance, and how the concept of inspiratory lungpower could be applied. The aim of this work was to study the patient inspiratory airflow profile performance in large data sets. We analyzed how the Kamin-Haidl inhalation criteria were met by patients with DPIs such as Easyhaler for combination therapy (EH-combi), Easyhaler for monotherapy (EH-mono), Diskus, and Turbuhaler (TH), and applied peak lungpower instead of peak inspiratory flow rate as an indicator of patient performance.Materials and Methods: Data sets gathered in two previous studies for DPIs, that is, EH-combi, EH-mono, Diskus, and TH, were used to analyze how inspiratory lungpower representing inspiratory muscle power, flow acceleration, and volume after peak met the inhalation criteria. The measured patient airflow profiles through inhalers were assessed for patients with asthma or COPD.Results: Based on the Kamin-Haidl inhalation criteria, successful inhalation requirements were met with EH-combi in 96.1% and with EH-mono in 92.6% of patients. The success rates were 89.5% and 84.6% with Diskus and TH, respectively, (p < 0.0001 between devices). In patients with asthma or COPD, the mean lungpower was 7.51 and 6.15 W for EH-combi, 8.79 and 6.88 W for EH-mono, 7.18 and 4.36 W for Diskus, and 9.65 and 6.86 W for TH, respectively, when patients followed the manufacturer's written instructions.Conclusions: Lungpower applied to the Kamin-Haidl inhalation criteria concept could be an applicable method for reviewing patient performance for different DPIs despite DPIs' characteristic differences in airflow resistance. In light of these results, DPIs provide a feasible treatment option for a large majority of respiratory patients.

Measurement site of inferior vena cava diameter affects the accuracy with which fluid responsiveness can be predicted in spontaneously breathing patients: a post hoc analysis of two prospective cohorts

BackgroundThe collapsibility index of the inferior vena cava (cIVC) has potential for predicting fluid responsiveness in spontaneously breathing patients, but a standardized approach for measuring the inferior vena cava diameter has yet to be established.The aim was to test the accuracy of different measurement sites of inferior vena cava diameter to predict fluid responsiveness in spontaneously breathing patients with sepsis-related circulatory failure and examine the influence of a standardized breathing manoeuvre.ResultsAmong the 81 patients included in the study, the median Simplified Acute Physiologic Score II was 34 (24; 42). Sepsis was of pulmonary origin in 49 patients (60%). Median volume expansion during the 24 h prior to study inclusion was 1000 mL (0; 2000). Patients were not severely ill: none were intubated, only 20% were on vasopressors, and all were apparently able to perform a standardized breathing exercise. Forty-one (51%) patients were responders to volume expansion (i.e. a ≥ 10% stroke volume index increase). The cIVC was calculated during non-standardized (cIVC-ns) and standardized breathing (cIVC-st) conditions. The accuracy with which both cIVC-ns and cIVC-st predicted fluid responsiveness differed significantly by measurement site (interaction p < 0.001 and < 0.0001, respectively). Measuring inferior vena cava diameters 4 cm caudal to the right atrium predicted fluid responsiveness with the best accuracy. At this site, a standardized breathing manoeuvre also significantly improved predictive power: areas under ROC curves [mean and (95% CI)] for cIVC-ns = 0.85 [0.78–0.94] versus cIVC-st = 0.98 [0.97–1.0], p < 0.001. When cIVC-ns is superior or equal to 33%, fluid responsiveness is predicted with a sensitivity of 66% and a specificity of 92%. When cIVC-st is superior or equal to 44%, fluid responsiveness is predicted with a sensitivity of 93% and a specificity of 98%.ConclusionThe accuracy with which cIVC measurements predict fluid responsiveness in spontaneously breathing patients depends on both the measurement site of inferior vena cava diameters and the breathing regime. Measuring inferior vena cava diameters during a standardized inhalation manoeuvre at 4 cm caudal to the right atrium seems to be the method by which to obtain cIVC measurements best-able to predict patients’ response to volume expansion.