Bart L. Rottier

Changes in performance of the Pari eFlow rapid and Pari LC Plus during 6 months use by CF patients.

BACKGROUND Nebulized antibiotics are important in the treatment of cystic fibrosis. The Pari eFlow rapid with vibrating mesh is often used off-label for the administration of tobramycin (TOBI) because of a reduced nebulization time and easier handling compared to a classic nebulizer-compressor combination. Mesh technology may be vulnerable, however. Therefore, we investigated particle size distribution and output as well as changes in the performance of the eFlow before and after 6 months of use, in comparison with the Pari LC Plus nebulizer plus Turboboy compressor. METHODS Size distributions in the aerosols and nebulization times for TOBI were measured with laser diffraction technique; delivered doses by weighing. RESULTS New eFlows produce considerably larger droplets (X(50) = 3.5 mum) from TOBI than new LC Plus nebulizers (X(50) = 2.8 mum). After use, the X(50) increases for both systems (to 3.7 and 3.3 mum, respectively). The relative span of the size distribution {(X(90)-X(10))/X(50)} changes from 1.26 to 1.28 mum for eFlow and from 2.19 to 2.45 mum for LC Plus. The total nebulization time doubles for LC Plus, whereas in 51% of all experiments the eFlow switched off after 10 min, resulting in incomplete dose delivery. For the eFlow, changes during use are related to clogging of orifices. Once being clogged, only replacement of the mesh restores the original performance. CONCLUSIONS New eFlows produce larger droplets and in a narrower size range compared to new LC Plus nebulizers for TOBI, and therefore both devices are not equivalent. Theoretically a larger portion of the aerosol from eFlow is likely to be deposited in the upper airways. The performance of both tested nebulizers decreases after 6 months of use. For the eFlow, timely replacement of the mesh is necessary. These in vitro results underscore the importance of registration studies of new drug-device combinations.

Monitoring asthma in children

The goal of asthma treatment is to obtain clinical control and reduce future risks to the patient. To reach this goal in children with asthma, ongoing monitoring is essential. While all components of asthma, such as symptoms, lung function, bronchial hyperresponsiveness and inflammation, may exist in various combinations in different individuals, to date there is limited evidence on how to integrate these for optimal monitoring of children with asthma. The aims of this ERS Task Force were to describe the current practise and give an overview of the best available evidence on how to monitor children with asthma. 22 clinical and research experts reviewed the literature. A modified Delphi method and four Task Force meetings were used to reach a consensus. This statement summarises the literature on monitoring children with asthma. Available tools for monitoring children with asthma, such as clinical tools, lung function, bronchial responsiveness and inflammatory markers, are described as are the ways in which they may be used in children with asthma. Management-related issues, comorbidities and environmental factors are summarised. Despite considerable interest in monitoring asthma in children, for many aspects of monitoring asthma in children there is a substantial lack of evidence. ERS statement summarising and discussing the available literature on monitoring children with asthma http://ow.ly/H01NG

Asthma medication delivery: mists and myths.

Asthma is usually treated with inhaled corticosteroids (ICS) and bronchodilators generated from pressurized metered dose inhalers (pMDI), dry powder inhalers (DPI), or nebulizers. The target areas for ICS and beta 2-agonists in the treatment of asthma are explained. Drug deposition not only depends on particle size, but also on inhalation manoeuvre. Myths regarding inhalation treatments lead to less than optimal use of these delivery systems. We discuss the origin of many of these myths and provide the background and evidence for rejecting them.

Comparative in vitro evaluation of four corticosteroid metered dose inhalers: Consistency of delivered dose and particle size distribution

INTRODUCTION Recent developments concerning pressurized metered dose inhalers (pMDIs) with inhaled corticosteroids (ICS) are the introduction of ciclesonide and the replacement of propellants. As the results of in vivo studies depend on pMDIperformance, it is necessary to evaluate pMDIs in vitro for delivered dose and particle size distributions under different conditions. METHODS Fluticasone 125microg, budesonide 200microg, beclomethasone HFA100microg, and ciclesonide 160microg were compared for delivered dose and particle size using laser diffraction analysis with inspiratory flow rates of 10, 20 and 30l/s. RESULTS The volume median diameter of budesonide was 3.5microm, fluticasone 2.8microm, beclomethasone and ciclesonide both 1.9microm. The mouthpiece retention was up to 30% of the nominal dose for beclomethasone and ciclesonide, 11-19% for the other pMDIs. Lifespan, flow rate, and air humidity had no significant influence on particle size distribution. The delivered dose of beclomethasone, budesonide, and ciclesonide remained constant over the lifespan. The delivered dose of fluticasone 125 decreased from 106% to 63%; fluticasone 250 also decreased whereas fluticasone 50 remained constant. CONCLUSIONS There is a significant difference in median particle size distribution between the different ICS pMDIs. Air humidity and inspiratory flow rate have no significant influence on particle size distribution. Ciclesonide 160 and beclomethasone 100 deliver the largest fine particle fractions of 1.1-3.1microm. The changes in delivered dose during the lifespan for the fluticasone 125 and 250 may have implications for patient care.

Anti-inflammatory drug therapy in asthma

Asthma is a disease with chronic inflammation of the airways and and-inflammatory treatment is a logical treatment. Inhaled corticosteroids [ICS] remain the cornerstone of anti-inflammatory therapy in recent international guidelines. Asthma cannot be cured by any medication: if the drug is discontinued, the disease manifestations return. This has been proven at all ages. In preschool children the diagnosis of asthma is difficult to establish. In this heterogeneous group ICS or leukotriene receptor antagonists [LTRA] are just as effective as placebo; in the future it will hopefully be possible to describe characteristics of responders. LTRA are an alternative in mild asthma, especially when mono-triggered viral related wheeze is present. Theophylline is effective and also has bronchodilatory properties, which need to be balanced against the relatively frequent side effects. The working mechanisms of anti-inflammatory asthma medications including ICS, LTRA, cromones, macrolides and theophylline are described.

Tolerance of Organ Transplant Recipients to Physical Activity during a High-Altitude Expedition : Climbing Mount Kilimanjaro

Background It is generally unknown to what extent organ transplant recipients can be physically challenged. During an expedition to Mount Kilimanjaro, the tolerance for strenuous physical activity and high-altitude of organ transplant recipients after various types of transplantation was compared to non-transplanted controls. Methods Twelve organ transplant recipients were selected to participate (2 heart-, 2 lung-, 2 kidney-, 4 liver-, 1 allogeneic stem cell- and 1 small bowel-transplantation). Controls comprised the members of the medical team and accompanying family members (n = 14). During the climb, cardiopulmonary parameters and symptoms of acute mountain sickness were recorded twice daily. Capillary blood analyses were performed three times during the climb and once following return. Results Eleven of the transplant participants and all controls began the final ascent from 4700 meters and reached over 5000 meters. Eight transplant participants (73%) and thirteen controls (93%) reached the summit (5895m). Cardiopulmonary parameters and altitude sickness scores demonstrated no differences between transplant participants and controls. Signs of hyperventilation were more pronounced in transplant participants and adaptation to high-altitude was less effective, which was related to a decreased renal function. This resulted in reduced metabolic compensation. Conclusion Overall, tolerance to strenuous physical activity and feasibility of a high-altitude expedition in carefully selected organ transplant recipients is comparable to non-transplanted controls.

Monitoring asthma in childhood: management-related issues.

Management-related issues are an important aspect of monitoring asthma in children in clinical practice. This review summarises the literature on practical aspects of monitoring including adherence to treatment, inhalation technique, ongoing exposure to allergens and irritants, comorbid conditions and side-effects of treatment, as agreed by the European Respiratory Society Task Force on Monitoring Asthma in Childhood. The evidence indicates that it is important to discuss adherence to treatment in a non-confrontational way at every clinic visit, and take into account a patients illness and medication beliefs. All task force members teach inhalation techniques at least twice when introducing a new inhalation device and then at least annually. Exposure to second-hand tobacco smoke, combustion-derived air pollutants, house dust mites, fungal spores, pollens and pet dander deserve regular attention during follow-up according to most task force members. In addition, allergic rhinitis should be considered as a cause for poor asthma control. Task force members do not screen for gastro-oesophageal reflux and food allergy. Height and weight are generally measured at least annually to identify individuals who are susceptible to adrenal suppression and to calculate body mass index, even though causality between obesity and asthma has not been established. In cases of poor asthma control, before stepping up treatment the above aspects of monitoring deserve closer attention. ERS review summarising and discussing the management-related issues regarding the monitoring of asthma in childhood http://ow.ly/JfjGs

Effect of inhaler design variables on paediatric use of dry powder inhalers

Age appropriateness is a major concern of pulmonary delivery devices, in particular of dry powder inhalers (DPIs), since their performance strongly depends on the inspiratory flow manoeuvre of the patient. Previous research on the use of DPIs by children focused mostly on specific DPIs or single inspiratory parameters. In this study, we investigated the requirements for a paediatric DPI more broadly using an instrumented test inhaler. Our primary aim was to assess the impact of airflow resistance on children’s inspiratory flow profiles. Additionally, we investigated children’s preferences for airflow resistance and mouthpiece design and how these relate to what may be most suitable for them. We tested 98 children (aged 4.7–12.6 years), of whom 91 were able to perform one or more correct inhalations through the test inhaler. We recorded flow profiles at five airflow resistances ranging from 0.025 to 0.055 kPa0.5.min.L−1 and computed various inspiratory flow parameters from these recordings. A sinuscope was used to observe any obstructions in the oral cavity during inhalation. 256 flow profiles were included for analysis. We found that both airflow resistance and the children’s characteristics affect the inspiratory parameters. Our data suggest that a medium-high resistance is both suitable for and well appreciated by children aged 5–12 years. High incidences (up to 90%) of obstructions were found, which may restrict the use of DPIs by children. However, an oblong mouthpiece that was preferred the most appeared to positively affect the passageway through the oral cavity. To accommodate children from the age of 5 years onwards, a DPI should deliver a sufficiently high fine particle dose within an inhaled volume of 0.5 L and at a peak inspiratory flow rate of 25–40 L.min−1. We recommend taking these requirements into account for future paediatric inhaler development.

Assessment of Controversial Pediatric Asthma Management Options Using GRADE

OBJECTIVES: To develop explicit and transparent recommendations on controversial asthma management issues in children and to illustrate the usefulness of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach in rating the quality of evidence and strength of recommendations. METHODS: Health care questions were formulated for 3 controversies in clinical practice: what is the most effective treatment in asthma not under control with standard-dose inhaled corticosteroids (ICS; step 3), the use of leukotriene receptor antagonist for viral wheeze, and the role of extra fine particle aerosols. GRADE was used to rate the quality of evidence and strength of recommendations after performing systematic literature searches. We provide evidence profiles and considerations about benefit and harm, preferences and values, and resource use, all of which played a role in formulating final recommendations. RESULTS: By applying GRADE and focusing on outcomes that are important to patients and explicit other considerations, our recommendations differ from those in other international guidelines. We prefer to double the dose of ICS instead of adding a long-acting β-agonist in step 3; ICS instead of leukotriene receptor antagonist are the first choice in preschool wheeze, and extra fine particle ICS formulations are not first-line treatment in children with asthma. Recommendations are weak and based on low-quality evidence for critical outcomes. CONCLUSIONS: We provide systematically and transparently developed recommendations about controversial asthma management options. Using GRADE for guideline development may change recommendations, enhance guideline implementation, and define remaining research gaps.

The influence of inhaled corticosteroids and spacer devices on the growth of respiratory pathogenic microorganisms.

BACKGROUND Guidelines advise weekly cleansing of spacers, with one of the reasons being to prevent the spacers from becoming colonized with respiratory pathogens. Earlier work in clinical settings showed conflicting results. METHODS Common respiratory pathogens and Candida albicans were applied on Petri dishes with and without inhaled corticosteroids and in 3 brands of spacer devices, with and without inhaled corticosteroids. Growth was measured. RESULTS After 24 hours, Staphylococcus aureus grew in 7 of 18 spacers (39%); Pseudomonas aeruginosa grew in 12 out of 18 spacers (67%); and C albicans survived in 5 of 18 spacers (28%). Microorganisms survived on Petri dishes with fluticasone and beclomethasone but not when budesonide was applied. One out of 30 metal Nebuhalers (3%) was colonized after 24 hours, whereas of 30 Volumatics 8 (27%) and Aerochambers, 17 (57%) still had viable microorganisms. Application of inhaled steroids did not affect growth in the spacers. CONCLUSION The colonization of metal spacers is lower than of spacers made of polycarbonate or polyethylene. C albicans can survive in spacers. The survival of microorganisms in spacers is not influenced by inhaled corticosteroids.