Aerosol therapy in young children

Inhalation of aerosolized drugs has become an established means for treatment of pulmonary diseases in the last fifiy years. The majoriry of aerosol therapy in childhood concerns inhaled corticosteroids and bronchodilators in the management of asthma. Administration of drugs via the inhaled route has major advantages over the oral route. The drug is targeted directly to its site of action, which results in a more rapid effect and a lower dose needed with less systemic side effects. However, to deliver the drug into the lungs reliably and reproducibly is difficult, especially in children. It requires understanding of the mechanisms of aerosol deposition in the lungs and knowledge about the factors affecting delivery and deposition of aerosols. There are several ways to deliver therapeutic aerosols to the lungs. The current methods can be classified in three categoties: nebulizers, pressurized metered dose inhales (pMDI's) with or without spacer, and dry powder inhalers (DPT's). Not all systems are suirable for use in young children. Application of aerosol therapy in young children requires a different approach compared vvith adults and older children. Factors such as age, co-operation, breathing pattern, nose breathing and size of the airways should be raken into account as they can have substantial effect on the dose delivered to the lungs. Nebulizers have long been the mainstay of aerosol therapy in children. Currently, the pMDI combined with spacer is recommended as the first choice for asthma therapy in young children. However, the pMDIIspacer and most other aerosol delivery systems were primarily designed for use in adults, and subsequently adapted for use in children. Furthermore, studying efficiency of aerosol delivery systems in young children is difficult and has ethical limitations. This explains why there is extended information available on the performance of aerosol delivery systems in adults, but only limited data in children. The use of drugs with potential side effects, such as corticosteroids, requires precise dosing with the administration of the lowest effective dose. Therefore, knowledge about the dose inhaled and factors affecting this dose for each particular drug, device and patient is necessary for optimal application of aerosol therapy. Better understanding of aerosol therapy in children is urgently needed

Extra-fine particles improve lung delivery of inhaled steroids in infants: a study in an upper airway model

BACKGROUND: The particles of a new hydrofluoroalkane-134a (HFA)-beclomethasone dipropionate (BDP) metered-dose inhaler (Qvar; 3M Pharmaceuticals; St. Paul, MN) are considerably smaller than those of chlorofluorocarbon (CFC)-BDP. This may improve lung deposition in infants who inhale nasally and have irregular breathing patterns and small airways. Aim: To compare the dose delivered to the lungs of HFA-BDP and CFC-BDP at different breathing patterns using an upper airway model of an infant. METHODS: An anatomically correct upper airway model of a 9-month-old child with an open nasal airway was connected to an impactor and breathing simulator. HFA-BDP, 100 microg, and CFC-BDP, 100 micro g, were delivered to the model through a detergent-coated, small-volume spacer. The total dose leaving the model (lung dose), its particle size distribution, and median mass aerodynamic diameter (MMAD) were assessed during simulated tidal breathing with tidal volumes (VTs) of 50 mL, 100 mL, and 200 mL, and 30 breaths/min. Dose was expressed as percentage of nominal dose. RESULTS: Lung doses for HFA-BDP were 25.4%, 26.5%, and 30.7% compared with 6.8%, 4.8%, and 2.1% for CFC-BDP at VTs of 50 mL, 100 mL, and 200 mL, respectively. The dose of particles < 2.1 microm to the lung for HFA-BDP was 23 to 28% compared with 0.6 to 0.8% for CFC-BDP. The lung dose of CFC-BDP mainly consisted of particles between 2.1 microm and 4.7 microm. MMAD for HFA-BDP was 1.2 microm, and 2.6 to 3.3 microm for CFC-BDP depending on VT. The lung dose for CFC-BDP decreased significantly with increasing VT. HFA-BDP lung dose did not alter significantly with VT. CONCLUSIONS: In this infant model study, the use of HFA-BDP with a high dose of particles < 2.1 microm improves the dose delivered to the lungs substantially. Furthermore, the large proportion of extra-fine particles in HFA-BDP results in lung doses less dependent on breathing pattern compared with CFC-BDP

Variability of aerosol delivery via spacer devices in young asthmatic children in daily life

Pressurized metered dose inhalers (pMDI) are widely used together with spacers for the treatment of asthma in children. However, the variability of daily medication dose for pMDI/spacer combinations is not known. Electrostatic charge is a potential source of dose variability. Metal spacers have no static charge. This study assessed and compared within-subject variability of aerosol delivery of metal and plastic spacers. This was a randomized, crossover study in children with stable asthma aged 1-4 (group I, n=17) and 5-8 (group II, n=16) yrs. In both groups the amount of drug delivered to the mouth by a metal spacer (Nebuchamber) and one of two plastic (polycarbonate) spacers, i.e. Babyhaler in group I and Volumatic in group II was measured. The metal and plastic spacers were tested at home in a randomized order for 7 days each, using budesonide (200 microg b.i.d.). Aerosol was collected on a filter positioned between spacer and facemask or mouth. Budesonide on the filter was assessed by high performance liquid chromatography. The mean filter dose for each child (mean+/-SD) during the 7 days was expressed as a percentage of the nominal dose. Within-subject variability was expressed as coefficient of variation (CV). Mean filter dose in group I was 41.7+/-10.1% for Nebuchamber and 26.0+/-4.0% for Babyhaler (p<0.001). Mean filter dose in group II was 50.2+/-9.2% for Nebuchamber and 19.4+/-7.2% for Volumatic (p<0.001). Mean CV in group I was 34% for Nebuchamber and 37% for Babyhaler (p=0.44). Mean CV in group II was 23% for Nebuchamber and 34% for Volumatic (p=0.003). There was substantial within-subject dose variability in aerosol delivery in children using a pMDI/spacer at home. This variability was lower for the metal than for the plastic spacer in children 5-8 yrs of age. The dose delivered to the mouth was about two-fold higher fo

Aerosol delivery from spacers in wheezy infants: a daily life study

The aims of this study were to assess and compare dose delivery and dose variability of pressurized metered dose inhalers (pMDI)/spacers in wheezy infants in daily life and to investigate factors influencing aerosol delivery. In an open randomized crossover study in 25 wheezy infants aged 5-26 months, a metal spacer (Nebuchamber), a detergent coated (DC) and a non-detergent coated (nonDC) plastic spacer (Babyhaler) were tested at home for 7 days each. Budesonide (200 microg b.i.d) was administered via a Nebuchamber or fluticasone (125 microg b.i.d) via a Babyhaler. Aerosol was trapped in filters, positioned between the spacer and face mask. Cooperation was scored on diary cards. Electrostatic charge (ESC) of the spacers was measured. Evaluations of the administration technique were made from video recordings. Median (range) dose delivery of the filters expressed as per cent (%) of nominal dose, was 34% (3-59), 23% (1-49), and 41% (12-55) for the Nebuchamber, nonDC-Babyhaler, and DC-Babyhaler respectively. Considerable dose variability was found, median (range) within-subject dose variability, expressed as coefficient of variation, for the Nebuchamber (49% (15-249)) was significantly higher when compared with both nonDC- (36% (12-325)) and DC-Babyhalers (27% (10-122)), for which dose variabilities were similar. Detergent coating was effective to reduce electrostatic

Airway disease on chest computed tomography of preschool children with cystic fibrosis is associated with school-age bronchiectasis

Airway wall thickening and mucus plugging are important characteristics of cystic fibrosis (CF) lung disease in the first 5 years of life.The aim of this study is to investigate the association of lung disease in preschool children (age, 2-6) with bronchiectasis and other clinical outcome measures in the school age (age >7). Deidentified computed tomography-scans were annotated using Perth-Rotterdam annotated grid morphometric analysis for CF. Preschool %disease (a composite score of %airway wall thickening, %mucus plugging, and %bronchiectasis) and %MUPAT (a composite score of %airway wall thickening and %mucus plugging) were used as predictors for %bronchiectasis and several other school-age clinical outcomes. For statistical analysis, we used regression analysis, linear mixed-effects models and two-way mixed models. Sixty-one patients were included. %Disease increased significantly with age (P .05). Cross-sectional, %disease in school-age was associated with a low FEV1% predicted and low quality of life (P =.01 and P =.007, respectively). %Disease can be considered an early marker of diffuse airways disease and is a risk factor for school-age bronchiectasis

Optimization and Dose Estimation of Aerosol Delivery to Non-Human Primates

Background: In pre-clinical animal studies, the uniformity of dosing across subjects and routes of administration is a crucial requirement. In preparation for a study in which aerosolized live-attenuated measles virus vaccine was administered to cynomolgus monkeys (Macaca fascicularis) by inhalation, we assessed the percentage of a nebulized dose inhaled under varying conditions. Methods: Drug delivery varies with breathing parameters. Therefore we determined macaque breathing patterns (tidal volume, breathing frequency, and inspiratory to expiratory (I:E) ratio) across a range of 3.3-6.5 kg body weight, using a pediatric pneumotachometer interfaced either with an endotracheal tube or a facemask. Subsequently, these breathing patterns were reproduced using a breathing simulator attached to a filter to collect the inhaled dose. Albuterol was nebulized using a vibrating mesh nebulizer and the percentage inhaled dose was determined by extraction of drug from the filter and subsequent quantification. Results: Tidal volumes ranged from 24 to 46 mL, breathing frequencies from 19 to 31 breaths per minute and I:E ratios from 0.7 to 1.6. A small pediatric resuscitation mask was identified as the best fitting interface between animal and pneumotachometer. The average efficiency of inhaled dose delivery was 32.1% (standard deviation 7.5, range 24%-48%), with variation in tidal volumes as the most important determinant. Conclusions: Studies in non-human primates aimed at comparing aerosol delivery with other routes of administration should take both the inter-subject variation and relatively low efficiency of delivery to these low body weight mammals into account

Generation of an induced pluripotent stem cell line (MHHi018-A) from a patient with Cystic Fibrosis carrying p.Asn1303Lys (N1303K) mutation

Cystic Fibrosis (CF) is a genetic disease caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene which encodes for a chloride ion channel regulating the balance of salt and water across secretory epithelia. Here we generated an iPSC line from a CF patient homozygous for the p.Asn1303Lys mutation, a Class II folding defect mutation. This iPSC line provides a useful resource for disease modeling and to investigate the pharmacological response to CFTR modulators in iPSC derived epithelia

Brand and generic use of inhalation medication and frequency of switching in children and adults: A population-based cohort study

Background: The expiration of patents of brand inhalation medications and the ongoing pressure on healthcare budgets resulted in a growing market for generics. Aim: To study the use of brand and generic inhalation medication and the frequency of switching between brand and generic and between devices. In addition, we investigated whether switching affected adherence. Methods: From dispensing data from the Dutch PHARMO Database Network a cohort aged ≥ 5 years, using ≥ 1 year of inhalation medication between 2003 and 2012 was selected. Switching was defined as changing from brand to generic or vice versa. In addition, we studied change in aerosol delivery device type (e.g., DPI, pMDI, and nebulizers). Adherence was calculated using the medication possession ratio (MPR). Results: The total cohort comprised 70,053 patients with 1,604,488 dispensations. Per calendar year, 5% switched between brand and generic inhalation medication and 5% switched between devices. Median MPRs over the first 12 months ranged between 33 and 55%. Median MPR over the total period was lower after switch from brand to generic and vice versa for formoterol (44.5 vs. 42.1 and 63.5 vs. 53.8) and beclomethasone (93.8 vs. 59.8 and 81.3 vs. 55.9). Conclusion: Per year, switching between brand and generic inhalation medication was limited to 5% of the patients, switching between device types was observed in 5% as well. Adherence to both generic and brand inhalation medication was low. Effect of switching on adherence was contradictory; depending on time period, medication and type, and direction of switching. Further research on reasons for switching and potential impact on clinical outcomes is warranted

Controlled evaluation of a transition clinic for Dutch young people with cystic fibrosis

Background: Transition clinics (TCs) are advocated as best practice to support young people with cystic fibrosis (CF) during transition to adulthood and adult care. We aimed to research the functioning of a TC for young people with CF compared with direct hand-over care and to evaluate whether those treated at the TC have better transfer experiences and outcomes compared with the control group. Methods: Mixed-methods retrospective controlled design, including interviews with professionals, observations of clinics, chart reviews (at four measurement moments), and patient surveys. Qualitative data analysis focused on organization and daily routines, and barriers and facilitators experienced. Young people's transfer experiences, self-management, health care use, and clinical outcomes were assessed quantitatively. Results: The most notable feature distinguishing the TC and direct hand-over care comprised joint consultations between pediatric and adult care professionals in the former. A transition coordinator was considered essential for the success of the TC. The main barriers were lack of time, planning, and reimbursement issues. Young people treated at the TC tended to have better transfer experiences and were more satisfied. They reported significantly more trust in their adult care professionals. Their self-management-related outcomes were less favorable. Conclusions: The TC had several perceived benefits and showed positive trends in transfer experiences and satisfaction, but no differences in health-related outcomes. Structured preparation of young people, joint consultations with pediatric and adult care professionals, and better coordination were perceived as facilitating elements. Further improvement demands solutions for organizational and financial barriers, and better embedding of self-management interventions in CF care

Exploratory Study of Signals for Asthma Drugs in Children, Using the EudraVigilance Database of Spontaneous Reports

Introduction: As asthma medications are frequently prescribed for children, knowledge of the safety of these drugs in the paediatric population is important. Although spontaneous reports cannot be used to prove causality of adverse events, they are important in the detection of safety signals. Objective: Our objective was to provide an overview of adverse drug events associated with asthma medications in children from a spontaneous reports database and to identify new signals. Methods: Spontaneous reports concern