Comparison of efficiency and preference of metal and plastic spacers in preschool children.

BACKGROUND: The metal NebuChamber valved holding chamber (VHC) has gained wide acceptance among children with asthma. Due to its nonelectrostatic properties and larger volume, the 250-mL, metal NebuChamber delivers a greater mass of aerosol to a filter at the mouth compared with the commonly used 150-mL polypropylene AeroChamber VHC. Such in vitro results have been used to suggest that this may provide increased efficacy with the NebuChamber. No comparative efficacy data exist for preschool children with asthma. OBJECTIVE: To compare efficiency and preference of metal and plastic spacers in preschool children. METHODS: Children with mild-to-moderate persistent asthma received 200 microg of budesonide twice daily by NebuChamber or AeroChamber, both with the mask provided in a randomized, 2-month, crossover trial. Symptom diary cards, beta-agonist use, and preference by children and parents were compared. RESULTS: Thirty children (mean +/- SD age, 4.3 +/- 0.3 years) completed the study. There was no difference between the AeroChamber and NebuChamber in clinical efficacy outcomes. There was no difference between the AeroChamber and NebuChamber in parents' view of ease of use, design, acceptability by the children, and overall satisfaction. CONCLUSIONS: Despite a greater total dose delivered to the mouth, the NebuChamber appears no more effective than the AeroChamber and it is not preferred by patients or parents. More parents chose to continue to use the NebuChamber after the study.

Protection against methacholine-induced bronchospasm: salbutamol pMDI versus Clickhaler DPI.

Passive dry-powder inhalers (DPIs) have been developed as an alternative to pressurised metered-dose inhalers (pMDIs) to improve aerosol delivery on inhalation and eliminate the need for propellants. However, new DPI formulations of generic drugs must be rigorously compared with conventional pMDI therapy. This randomised, double-blind, double-dummy, placebo-controlled, seven-way crossover study evaluated bronchoprotection from methacholine challenge in order to compare a novel salbutamol DPI (Clickhaler) with a reference salbutamol pMDI (Ventolin). Adult asthma patients with airway hyperresponsiveness to methacholine (provocative concentration of methacholine causing a 20% fall in the forced expiratory volume in one second (PC20) <4 mg x mL(-1)) were treated on separate days with 0, 100, 200 or 400 microg of salbutamol via the DPI or pMDI. Methacholine challenge was performed before and after salbutamol treatment and the PC20 ratios analysed by Finney's bioassay to test for therapeutic equivalence of the inhalers. Eighteen patients completed the study and showed significant dose-related responses to salbutamol. The relative potency of DPI:pMDI was 1.29 (90% confidence interval 1.04-1.63). There were no treatment differences in safety (cardiac frequency, blood pressure, adverse events). Methacholine-challenge methodology provides a sensitive bioassay and has demonstrated therapeutic equivalence of the salbutamol Clickhaler dry-powder inhaler with the conventional salbutamol pressurised metered-dose inhaler.

Safety of inhaled corticosteroids delivered by plastic and metal spacers.

BACKGROUND: Because of its non-electrostatic properties the metal Nebuchamber (NC) valved holding chamber (VHC) delivers a greater mass of aerosol to the mouth than the polypropylene Aerochamber (AC) VHC. Delivery of more aerosol to the lungs may also increase systemic absorption of inhaled corticosteroids (ICS) and hypothalamo-pituitary-adrenal (HPA) suppression. METHODS: Thirty children (mean 4.3 (SD 0.3) years) received 200 micro g budesonide twice daily by NC or AC, both with the mask provided, in a randomised, two month crossover trial. Twenty four hour urinary free cortisol (UFC) was determined as a measure of HPA suppression. RESULTS: UFC decreased from 42.3 (7.8) nmol UFC/nmol creatinine control to 26.2 (2.4) (p = 0.06 v control) after AC, and to 24.5 (2.5) (p = 0.04 v control) after NC (p = 0.4 AC v NC). CONCLUSIONS: Despite a greater total dose delivered to the mouth, NC is not associated with greater HPA suppression when using 400 micro g/day budesonide under real life conditions in young children.

Aerosols for systemic delivery of macromolecules.

During the past 50 years, aerosol therapy with small molecules has become the mainstay for managing lung diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. During the past decade, a new therapeutic paradigm has evolved-the delivery of macromolecules into the systemic circulation through the lung. Systemic pulmonary therapy with proteins and peptides resulted from major developments in dry powder drug formulations and aerosol delivery technology. These new technologies will enable the treatment of systemic disease, such as diabetes mellitus, noninvasively by means of the deep lung. Within a decade, it is likely that many medications will be administered in this way.

Aerosol therapy with valved holding chambers in young children: importance of the facemask seal.

OBJECTIVE: Masks are an essential interface between valved holding chambers (VHCs), or spacers, and a small child's face for providing aerosol therapy. Clinical experience suggests that many young children do not cooperate with the VHC treatment or tolerate a mask of any kind. This might impair the mask-face seal and reduce the dose delivered to the child. The objective of this study was to evaluate the ability of parents to provide a good mask-face seal in infants and toddlers using 3 masks provided with commonly used pediatric VHCs and compare this with the seal obtained with the Hans Rudolph pediatric anesthesia mask. METHODS: A preliminary in vitro filter study was conducted to validate the assumption that reduced ventilation as a result of increased facemask leak reduces the drug aerosol dose delivered to the mouth. Facemask leak then was studied in vivo for NebuChamber, AeroChamber, BabyHaler, and Hans Rudolph masks by measuring ventilation with an in-line pneumotachograph while the facemask was held in place by experienced parents who were asked to demonstrate how they deliver medication to their children without any additional instruction. Thirty children (mean age: 3.2 +/- 1.4 years) performed 4 repeat studies with each mask. The first 10 patients performed the tests once again within 1 month. On the second occasion, the parents were coached continuously and encouraged to hold the mask tightly against the child's face. RESULTS: The AeroChamber and Hans Rudolph masks provided the best seal as reflected in the magnitude of the ventilation measured through them. The NebuChamber provided the poorest seal, with 45% less ventilation than the AeroChamber and Hans Rudolph masks. There was considerable intraindividual variability for all masks (24% to 48%); however, the variability with the NebuChamber mask was 2-fold greater than the other masks. All ventilatory volumes during the coached session were significantly greater than during the uncoached session. Variability during the coached session was significantly less (except for the BabyHaler, which remained unchanged). CONCLUSIONS: VHCs with masks designed for use with small children may provide a poor seal with the face, leading to reduced or more variable dose delivery. The facemask seal is critical for efficient aerosol delivery to infants and young children, and this should be stressed to parents.

Laser resection of a pedunculated tracheal adenoma.

We report a case of tracheal adenoma presenting as hemoptysis and reversible airflow obstruction in an ex-smoker. A questionable defect in the tracheal air shadow on a posteroanterior chest radiograph was shown on CT to be a pedunculated, mid-tracheal tumor. Two-stage bronchoscopic laser resection resulted in an apparently normal tracheal mucosa. Results of postresection spirometry were normal.

Lung deposition and clearance of inhaled (99m)Tc-heparin in healthy volunteers.

The purpose of this study was to quantify the lower respiratory tract (LRT) dose delivered by a single nebulization of (99m)technetium-labeled sodium heparin as well as its airway distribution, and kinetics of aerosol clearance, since inhaled heparin may be useful in the treatment of asthma. Fifteen healthy subjects (5 male, 10 female) inhaled heparin from a jet nebulizer loaded with 90,000 IU of (99m)Tc-heparin, driving flow rate 10 L/min. Lung scintigrams and blood samples were taken immediately and at several time points up to 24 h after inhalation. 15 +/- 3% (mean +/- SD) (mean 13,300 IU) of the heparin nebulizer charge reached the mouth, and 8 +/- 2% (mean 7,000 IU) was found in the LRT. Jet nebulizer residual was 48 +/- 6% (mean 43,000 IU), 32 +/- 4% (mean 29,000) was found on exhalation filters, and 5 +/- 2% in the tubing. (99m)Tc-heparin was distributed uniformly in the lungs, and clearance was biphasic. 39 +/- 8% of the LRT dose of (99m)Tc-heparin remained in the lungs 24 h after inhalation. 10.00 +/- 3.40% (687 +/- 310 IU) of the LRT dose or 0.76 +/- 0.35% of the nebulizer charge was found in the blood. Peak concentration in the blood was found 61 +/- 25 min after conclusion of inhalation, which took 15 min. We conclude that a small but significant fraction of nebulized heparin reaches the LRT. The inhaled heparin distributes uniformly in the lungs from which it clears slowly, making it suitable for local administration without induction of measurable changes in coagulation assays. Administration of the present single dose of heparin thus appears to be safe.

Dry powder versus intravenous and nebulized gentamicin in cystic fibrosis and bronchiectasis. A pilot study.

Aminoglycosides are a mainstay of therapy for patients with cystic fibrosis (CF) or non-CF bronchiectasis who are infected with Pseudomonas aeruginosa (Psa). Traditionally, aerosolized antibiotics are delivered by liquid nebulization. The objective of this study was to determine whether a gentamicin dry powder inhaler (DPI) is as microbiologically active and potentially safe as gentamicin inhaled via a small-volume nebulizer (SVN) or given intravenously. The study was done according to a randomized, single-dose, and triple crossover protocol. Ten patients with CF or non-CF bronchiectasis and chronically infected with Psa were recruited. Patients received a single dose of either gentamicin 160 mg via DPI or SVN, or gentamicin at 5 mg/kg by intravenous infusion. In seven of the 10 patients, the minimum inhibitory concentration (MIC) was achieved in sputum after DPI and SVN, with mean (95% confidence interval) gentamicin concentrations at 2 h after administration of 13.1 microgram/g sputum (range: 2.2 to 23.9 microgram/g) and 97.2 microgram/g sputum (range: 0.3 to 194.2 microgram/g), respectively, whereas gentamicin levels in the sputum after intravenous administration failed to reach the MIC. Gentamicin given by DPI and SVN significantly decreased the sputum Psa density (p < 0.05), by almost one order of magnitude. No significant decline in bacterial counts was observed after intravenous gentamicin. When gentamicin was inhaled, blood concentrations were minimal, and were below concentrations known to cause systemic toxicity. For treatment of Psa infections susceptible to gentamicin, gentamicin administration by DPI appeared to be as efficient as by SVN, despite the delivery of a 7-fold lower dose to the airways.

Inspiratory flow rates through a novel dry powder inhaler (Clickhaler) in pediatric patients with asthma.

Inspiratory flow profiles through a novel dry powder inhaler (DPI) (Clickhaler; Innovata Biomed Ltd, St. Albans, UK) were recorded in 17 pediatric patients (aged 7-16 years) with stable mild to moderate asthma. Most patients (n = 14) could generate high peak inspiratory flows (PIFs) (> 60 L/min) and high flows early in the flow profile. These flows have been shown to be adequate to deaggregate and deliver micronized drug with this delivery system.

Characterization of heparin aerosols generated in jet and ultrasonic nebulizers.

Inhaled heparin has been used for asthma treatment, but results have been inconsistent, probably due to highly varying lung doses. We determined the output per unit time and the particle size distributions of sodium heparin, calcium heparin, and low molecular weight (LMW) heparin formulations in five concentrations from Sidestream jet nebulizers (Medic-Aid, Bognor Regis, England) and an Ultraneb 2000 ultrasonic nebulizer (DeVilbiss, Langen, Germany). We also determined the inhaled mass and the estimated respirable mass for some combinations. For the jet nebulizer, output per minute increased with increasing concentration and flow rate, and particle size decreased from 3.64 to 2.01 microns (mass median diameter [MMD]). The percentage of particles less than 3 microns ranged from 41% to 74%. For the ultrasonic nebulizer, maximum output per minute was achieved at a concentration of 7000 i.u./mL; this maximum depended upon the viscosity and temperature of the solution. MMD was independent of formulation, temperature, or concentration and ranged from 5.61 to 7.03 microns. Sodium heparin/calcium heparin in a concentration of 20,000 i.u./mL in the jet nebulizer driven at 10 L/min produced the highest dose of heparin capable of reaching the lower respiratory tract. Mass balance was determined for these combinations with the jet nebulizer run until visible aerosol generation ceased. Of a loading dose of 80,000 i.u. of heparin, 45,000 i.u. remained in the dead space of the nebulizer, 20,000 i.u. was deposited on the exhalation filter, and 15,000 i.u. was captured on the inhalation filter (inhaled mass). This corresponds to a respirable mass of 10,000 i.u. of heparin with a high probability of reaching the lower respiratory tract in normal healthy adults.

A randomized controlled trial on the effect of inhaled corticosteroids on airways inflammation in adult cigarette smokers.

STUDY OBJECTIVE: To determine whether inhaled corticosteroid treatment can reduce airways inflammation in adult cigarette smokers. DESIGN: This was a randomized, placebo-controlled, double-blinded clinical trial. SETTING: The subjects were recruited from the community by advertising. PARTICIPANTS: Seventy-one adults with a > or = 5 pack-year history who were current smokers, had a normal FEV1, and produced sputum daily. INTERVENTION: Sixty subjects were randomized to receive four puffs of placebo or beclomethasone dipropionate ([BDP]; total dosage, 1,000 microg/d) using a metered-dose aerosol inhaler with a valved holding chamber (AeroChamber; Trudell Medical; London, Ontario, Canada) for 28 days. MEASUREMENTS AND RESULTS: Eleven subjects were not randomized because of poor compliance. The primary outcome was fractional airway neutrophilia, as assessed by a differential cell count of sputum. Additional outcome measures were spirometry, measurement of airway responsiveness by methacholine challenge, and lung epithelial permeability measured by the clearance of radiolabeled diethylenetriamine pentaacetic acid. There were no significant differences between the two groups in any outcome measurement after 4 weeks of treatment. CONCLUSIONS: With normal spirometry, we found no benefit of treatment with inhaled BDP, 1,000 microg/d, on noninvasive measures of airways inflammation in adult smokers. This indicates that cigarette smoke-induced inflammation in its early stages (before a demonstrable airflow obstruction) is not steroid sensitive. This may occur because the site of involvement is not accessible to inhaled medications or because the inflammatory process is resistant to moderate doses of inhaled corticosteroids.

Clickhaler (a novel dry powder inhaler) provides similar bronchodilation to pressurized metered-dose inhaler, even at low flow rates.

STUDY OBJECTIVE: Comparison of the bronchodilator response to an albuterol novel dry powder inhaler (DPI) (Clickhaler [CH]; ML Laboratories PLC; St. Albans, UK) activated at various inspiratory flow rates and to an albuterol pressurized metered-dose inhaler (pMDI) by patients with moderate to moderately severe stable asthma. DESIGN: Randomized, double-blind, placebo-controlled comparison of the bronchodilator response to albuterol DPI (200 microg) at inspiratory flow rates of approximately 15, 30, and 60 L/min in patients with stable asthma with demonstrated reversibility to albuterol. Active (albuterol via pMDI inhaled at 30 L/min) and placebo controls were included. SETTING: Single center study at the chest/allergy unit of a teaching hospital in Canada. PATIENTS: Sixteen patients with moderate to moderately severe stable asthma. MEASUREMENTS AND RESULTS: Efficacy end points were FEV1, FVC, FEV1/FVC, maximum expiratory flow, and forced expiratory flow between 25% and 75% of vital capacity. Safety end points included heart rate, BP, and tremor. There was no significant difference between the bronchodilator response to albuterol via the CH at 15, 30, and 60 L/min inspiratory flow rate and, at all flow rates, no significant difference was found comparing albuterol CH with the pMDI. All of the techniques for delivering albuterol provided significantly better bronchodilatation than placebo. Adverse events were minimal and did not differ between CH and pMDI or between the various flow rates inhaled through the CH. CONCLUSION: A novel passive albuterol DPI (CH) provides a similar bronchodilator response at 15, 30, and 60 L/min inspiratory flow rates compared with a pMDI used optimally.

Hemoptysis due to MDI therapy in a patient with permanent tracheostomy: treatment with mask AeroChamber.

Persistent minor hemoptysis resulted from extensive granulation tissue on the main carina and adjacent bronchi due to frequent spraying of metered-dose inhaler (MDI)-generated aerosol medications directly into a permanent tracheostomy. Salbutamol, containing oleic acid, was considered the most likely cause. After an AeroChamber equipped with an infant mask was interposed between the MDI and the tracheal stoma, hemoptysis and the pathologic changes gradually resolved.

Metered-dose inhaler accessory devices in acute asthma: efficacy and comparison with nebulizers: a literature review.

OBJECTIVES: To evaluate the current literature about the efficacy of providing inhaled medications by metered-dose inhalers and accessory devices (MDI/ADs) to children with acute asthma and to compare it with the current standard of care, small-volume nebulizers (SVNs). DATA SOURCES: Online computer and manual searches in English-language journal articles published between 1980 and 1996. STUDY SELECTION: Seventeen prospective clinical trials that have used MDI/ADs in the treatment of acute asthma in children were retrieved. Ten randomized controlled studies that included a comparison with SVN treatment were selected. DATA EXTRACTION: Studies were assessed qualitatively by their subject characteristics, design, intervention procedures, outcome measures, and results. DATA SYNTHESIS: There were marked variations in types of MDI/ADs and in doses administered between and within studies. Major outcome measures included pulmonary function measurements and clinical scores. All studies found MDI/ADs to be effective in the treatment of infants and children with acute asthma. Among those who compared this treatment with SVN, 2 found the MDI/AD superior and the rest found it as effective as the SVN. CONCLUSIONS: The data support the effectiveness of MDI/ADs as first-line treatment in acute childhood asthma. In view of clinical benefit, safety, lower cost, personnel time, and speed and ease of administration of MDI/ADs compared with SVNs, MDI/ADs should be considered the preferred mode of treatment of children with acute asthma.