True adherence with the Turbuhaler in young children with asthma.

OBJECTIVE: To investigate true adherence with a dry powder inhaler, the Turbuhaler (TBH), in children with asthma. True adherence was calculated by multiplying adherence to treatment with inhaler competence, that is correct use of the inhaler. PATIENTS AND DESIGN: In an 18-month study, children aged 5-10 years with asthma received twice daily budesonide via a TBH. Parents and children were trained in the correct use of the inhaler before the study started. For each inhalation, peak inspiratory flow through the TBH (PIF(TBH)) was recorded with an electronic pneumotachograph. The PIF(TBH) recordings were used to calculate true adherence for the first and last 45-day periods in the study by multiplying adherence in using the device (percentage of days with PIF(TBH) recordings) with inhaler competence (correct use of inhaler defined as PIF(TBH) values >40 l/min). MAIN OUTCOME MEASURES: True adherence, adherence, inhaler competence and PIF(TBH). RESULTS: 115 children were treated. The mean (morning and evening) true adherence during the first 45 days was 81.6% (range 78.1-86.4%) and during the last 45 days 57.4% (44.0-66.9%). Mean adherence was 86.0% and 59.3%, whereas mean inhaler competence was 94.7% and 96.2%, respectively. Thus the decline in true adherence was due to the decline in adherence. The largest decline in true adherence occurred in older children. CONCLUSIONS: True adherence with budesonide TBH treatment decreased significantly during the 18-month study due to a decrease in adherence. Inhaler competence with the correct use of the budesonide TBH was high and unchanged over the study period.

Daily versus as-needed inhaled corticosteroid for mild persistent asthma (The Helsinki early intervention childhood asthma study).

OBJECTIVE: To compare the effect of inhaled budesonide given daily or as-needed on mild persistent childhood asthma. Patients, design and INTERVENTIONS: 176 children aged 5-10 years with newly detected asthma were randomly assigned to three treatment groups: (1) continuous budesonide (400 microg twice daily for 1 month, 200 microg twice daily for months 2-6, 100 microg twice daily for months 7-18); (2) budesonide, identical treatment to group 1 during months 1-6, then budesonide for exacerbations as needed for months 7-18; and (3) disodium cromoglycate (DSCG) 10 mg three times daily for months 1-18. Exacerbations were treated with budesonide 400 microg twice daily for 2 weeks. MAIN OUTCOME MEASURES: Lung function, the number of exacerbations and growth. RESULTS: Compared with DSCG the initial regular budesonide treatment resulted in a significantly improved lung function, fewer exacerbations and a small but significant decline in growth velocity. After 18 months, however, the lung function improvements did not differ between the groups. During months 7-18, patients receiving continuous budesonide treatment had significantly fewer exacerbations (mean 0.97), compared with 1.69 in group 2 and 1.58 in group 3. The number of asthma-free days did not differ between regular and intermittent budesonide treatment. Growth velocity was normalised during continuous low-dose budesonide and budesonide therapy given as needed. The latter was associated with catch-up growth. CONCLUSIONS: Regular use of budesonide afforded better asthma control but had a more systemic effect than did use of budesonide as needed. The dose of ICS could be reduced as soon as asthma is controlled. Some children do not seem to need continuous ICS treatment.

Induced sputum in children with newly diagnosed mild asthma: the effect of 6 months of treatment with budesonide or disodium cromoglycate.

BACKGROUND: There are few controlled studies on the effects of anti-inflammatory treatment on airway inflammation in newly diagnosed childhood asthma. METHODS: Sixty children with newly diagnosed mild persistent asthma, 5-10 years of age, and 17 healthy control subjects were studied. Asthmatic children were randomized into an open study with two treatment groups: (1) budesonide 400 microg twice daily for 1 month, 200 microg twice daily for 5 months and (2) disodium cromoglycate (DSCG) 10 mg three-times daily for 6 months. All exacerbations were treated with budesonide 400 microg twice daily for 2 weeks. Symptoms and lung function were recorded throughout the study. RESULTS: Sputum induction was safe and the overall success rate was 71%. This improved with age and decreased after treatment. At baseline, the asthmatic children had more eosinophils in blood (0.26 vs 0.18 x 10(9)/l, P = 0.03) and sputum (1.1 vs 0.0 %, P = 0.0001) than the control subjects. The numbers of sputum eosinophils correlated with bronchial responsiveness (R = -0.58, P = 0.0002). Eosinophils were higher in children with atopic asthma than with nonatopic asthma (P < 0.0001), and in children with a history wheezing than in children without wheezing (P = 0.02). Six months of budesonide treatment, but not of DSCG, improved lung function (P = 0.007), decreased symptoms (P = 0.007) and sputum eosinophils (P = 0.003). The effects of budesonide were pronounced in children with intense sputum eosinophilia (>3%). CONCLUSION: Sputum eosinophilia is present in children with newly diagnosed mild persistent asthma. Treatment with inhaled budesonide, but not with DSCG, decreases sputum eosinophils along with clinical and functional improvement.

Adaptive Aerosol Delivery (AAD) technology.

Jet nebulisers have, since the 1920s, been used for delivery of inhaled drugs for the treatment of asthma, chronic-obstructive pulmonary disease and pulmonary infections. During the last two decades, recognition of the shortcomings of conventional nebulisers has led to the development of new "intelligent" nebulisers such as the Adaptive Aerosol Delivery (AAD), Profile Therapeutics, a Respironics company) systems. Diseases of the airways have traditionally been logical candidates for treatment with inhaled drugs. The introduction of the "intelligent" nebulisers has, however, broadened the possibilities for inhaled treatment to include drugs targeted for systemic diseases. These nebulisers offer the possibility to deliver more precise doses of drug, maximise lung deposition, enhance adherence to treatment and compliance with the device through feedback to the patient, and last but not least, offer the possibility to reduce nebulisation times.

Acceptability, reproducibility, and sensitivity of forced expiratory volumes and peak expiratory flow during bronchial challenge testing in asthmatic children.

OBJECTIVES: To compare the acceptability, reproducibility, and sensitivity of spirometric outcome measures of airway caliber during challenge testing in children. DESIGN: FEV(1), forced expiratory volume in 0.75 s, forced expiratory volume in 0.5 s, and peak expiratory flow (PEF) were recorded during stepwise dosimetric histamine challenge tests. The responses were compared, and the reproducibility at baseline and from duplicate measurements at each challenge step was determined. PATIENTS: One hundred five children with newly diagnosed asthma, aged 5 to 10 years. RESULTS: Compared to PEF, FEV(1) showed better baseline reproducibility (p = 0.002) and higher sensitivity (p < 0.0001) during challenge testing, determined as the change normalized to the baseline variation, while the forced expiratory volumes were not significantly different in these respects. During challenge testing in subjects with acceptable flow-volume tracings, paired recordings of FEV(1) agreed within 0.1 L in 85% and within 0.2 L in 93% of measurements. During challenge testing, the reproducibility of FEV(1) measurements was not better than that of the other indexes. Failure to exhale long enough precluded the use of FEV(1) in 16 of the children, particularly the youngest children. CONCLUSIONS: The results demonstrated that the recently published guidelines for FEV(1) measurements during challenge tests can be applied to children. During challenge tests in asthmatic children, the advantage of the shorter fractions of forced expiratory volume was that they were more often acceptably recorded than FEV(1), while they showed as good reproducibility and were also equally sensitive in assessing changes in airway obstruction.

Breathing patterns and aerosol delivery: impact of regular human patterns, and sine and square waveforms on rate of delivery.

In vitro tests are commonly employed to assess nebulizer performance. Whether the square or sine waveforms employed during in vitro tests could alter the nebulizer performance compared to that observed when a patient breathes through the nebulizer is debatable. Accordingly, the aim of this in vitro study was to compare the rates of delivery from nebulizers with simulated human breathing patterns to those obtained with matching sine and square waveforms. Regular human breathing patterns with tidal volumes (VT) of approximately 40, approximately 200, approximately 500, and approximately 800 mL were selected. Sine and square waveforms that matched the VT, peak inspiratory flow rate (PIF), breathing frequency (f), and inspiratory duty cycle (t(i)/t(tot)) of the human breathing patterns were created with a breathing simulator. The rate of delivery of nebulized technetium-99m-labeled diethylenetriamine pentaacetic acid (99mTC-DTPA) from two different jet nebulizer brands was determined. The rate of delivery was defined as the amount of the 99mTC-DTPA deposited during 30 sec of nebulization on a filter placed between the nebulizer and the breathing simulator. The rate of delivery of 99mTC-DTPA with the human breathing pattern was similar to that measured with the matching sine or square waveforms for either nebulizer. The configuration of the breath (PIF, VT, f, t(i)/t(tot)) did, however, influence the rate of delivery. In conclusion, the shape of the waveform, in other words, one resulting from a human breathing pattern, or a matching sine or square waveform, did not influence the rate of 99mTC-DTPA delivery from a nebulizer in vitro.

Nebulized budesonide after hospitalization for recurrent bronchial obstruction in children younger than 18 months.

A multi-center, double-blind, randomized dose-response study was performed to assess the effect of 3 months of treatment with two different doses of inhaled nebulized budesonide in children with acute recurrent bronchial obstruction (BO) causing hospitalization. Steroid-naive children younger than 18 months were included when admitted to hospital because of BO for at least the second time, and were followed-up monthly for 15 months. Forty-five of 49 subjects (43 boys, 2 girls) (mean age 9.3 months upon inclusion) completed the study. Twenty-four patients (20 boys, 4 girls) received nebulized budesonide 0.5 mg twice daily for 1 month followed by 0.25 mg daily for the next 2 months, whereas 25 children received 0.1 mg twice daily throughout the 3-month treatment period. Outcome (number of BO episodes, time to first BO after start of treatment, and use of rescue medication), as well as height/length and weight, were assessed at the start of treatment and monthly for the following 3 months, as well as for 12 months after cessation of treatment (15 months in total). There was an overall tendency towards better symptom control (fewer episodes of acute BO during treatment and follow-up, fewer hospital visits because of acute BO, lower clinical score during follow-up, and less use of rescue medication during follow-up) in the high-dose treatment group vs. the low-dose treatment group. However, the differences did not reach statistical significance for any of the outcomes. The only significant difference in effect between the groups was fewer children in the high-dose group treated openly with nebulized budesonide during follow-up. Length/height and weight gain did not differ significantly between the two treatment groups throughout the study. There was no significant dose-dependent beneficial effect of 3 months of treatment with nebulized budesonide in infants and toddlers with at least two hospitalizations for acute bronchial obstruction.

Nebulization of a suspension of budesonide and a solution of terbutaline into a neonatal ventilator circuit.

METHODS: The amount of nebulized budesonide and terbutaline delivered through an endotracheal tube (ETT) was measured in vitro using a test lung and filters in a neonatal ventilator circuit. Budesonide suspension (1 mg) was used in a concentration of 0.5 mg/mL and terbutaline solution (5 mg) in a concentration of 2.5 mg/mL. RESULTS: The median amount of terbutaline deposited on the inspiratory filters was significantly higher than that of budesonide: 0.4% vs 0.3% of the nominal doses with the nebulizer connected 8 cm upstream of the ETT and nebulization performed in a constant output mode (setup A), and 2.8% vs 1.0% with the nebulizer connected directly to the ETT and nebulization performed in a breath-synchronized mode (setup B) (p < 0.05 for both). The corresponding amounts of drug deposited on the waste filters with setup A were 19.2% for terbutaline and 12.6% for budesonide, and with setup B 16.2% for terbutaline and 6.2% for budesonide (p < 0.05 for both). CONCLUSIONS: The ratio between drug delivery to the inspiratory and waste filters, describing the relationship between lung deposition and wastage of drug to the ventilator circuit, was setup-dependent but not drug-dependent. The ratio with setup A was 0.02 for both budesonide and terbutaline. The respective ratios were significantly (p < 0.05) higher for budesonide (0.16) and for terbutaline (0.17) with setup B. The differences in the delivered doses of the two drugs through the ETT seems to be a function of both the drug formulation and the nebulizer-ETT setup. With the nebulizer connected directly to the ETT and nebulization in breath-synchronized mode, the differences between the two drugs were enhanced, compared with the nebulizer connected upstream of the ETT and nebulization in constant output mode. The results indicate that a solution is superior to a suspension in terms of drug delivery through an ETT.

Breath-synchronized nebulization diminishes the impact of patient-device interfaces (face mask or mouthpiece) on the inhaled mass of nebulized budesonide.

The choice of patient-device interface (face mask or mouthpiece) influences the inhaled mass and the lung deposition of nebulized drugs. The use of a mouthpiece has been shown to double the lung deposition compared with use of a face mask. We have determined the inhaled mass of budesonide using a jet nebulizer with mouthpiece in either a constant output or breath-synchronized mode in children. We have also determined the inhaled mass when the jet nebulizer is used with a nonsealing face mask in a constant output mode. The study was a 1-day, randomized, crossover, single-center study involving 158 asthmatic children (age range 5.1-15.7 years). Nebulized budesonide was administered in three single nominal doses of 1.0 mg by means of a jet nebulizer. The inhaled mass of budesonide was defined as the amount of drug deposited on filters positioned between the nebulizer and the mouthpiece or face mask. The mean inhaled mass of budesonide from different age groups ranged from 1 7.1% to 21.6% of the nominal dose with breath-synchronized nebulization with a mouthpiece. With constant output nebulization with a mouthpiece, the mean inhaled mass ranged from 8.9% to 12.2%, and with a nonsealed face mask the mean inhaled mass ranged from 5.0% to 6.9%. For children using jet nebulizers with mouthpiece, breath-synchronized nebulization appears to be superior to conventional constant output nebulization. The use of jet nebulizers with nonsealing face masks should be avoided.

Validation of a new breathing simulator generating and measuring inhaled aerosol with adult breathing patterns.

The use of breathing simulators for the in vitro determination of the inhaled mass of drug from nebulizers has become widely accepted. Their use is, however, based on the assumption that there is a correlation between the in vitro and in vivo inhaled mass of drug. The aim of the study was therefore to investigate whether a new breathing simulator--the MIMIC Breathing Emulator (Medic-Aid Limited, Bognor Regis, UK)--could accurately emulate the in vivo inhaled mass of budesonide suspension for nebulization. Eight adult healthy subjects were included. Each subject inhaled for 2 min from a Spira Module 1 jet nebulizer (Respiratory Care Center, Hämeenlinna, Finland), charged with 1.0 mg of budesonide suspension for nebulization (0.5 mg mL-1, 2 mL suspension, AstraZeneca, Sweden) and supplied with an inhaled mass filter between the nebulizer and the subject. The breathing patterns were recorded during the nebulization and simulated in vitro at two different experimental sites (simulations A and B) with the breathing simulator. With the patients breathing through the filters (in vivo test), inhaled mass of budesonide averaged 103.6 micrograms. The two in vitro experiments using the simulator revealed similar results with in vitro simulation A equal to 101.0 micrograms and simulation B 99.1 micrograms. There were no statistically significant differences between the in vivo results and those of in vitro simulation A. Results were significantly different for simulation B (p = 0.032) although the difference was less than 4.5%. These data indicate that the breathing simulator can be used to accurately simulate sine waveforms, human breathing patterns, and the in vitro and in vivo inhaled mass of budesonide suspension for nebulization.

Evaluation of pulsed and breath-synchronized nebulization of budesonide as a means of reducing nebulizer wastage of drug.

The aim of this open, randomized, crossover study was to compare the inhaled mass of budesonide suspension delivered by nebulization, using constant output, breath-synchronized, or pulsed jet nebulization techniques. The inhaled mass was defined as the amount of drug deposited on a filter between the inspiratory port of the nebulizer and the face mask or mouthpiece used by the subjects. The breath-synchronized nebulization delivered aerosol during the whole inspiration, whereas the pulsed nebulization was adjusted to deliver aerosol for up to 1 sec from the start of inspiration. Budesonide suspensions, 2 mL of 0.5 mg mL(-1), or 2 mL of 0.25 mg mL(-1), in single-dose respules, were used (AstraZeneca R&D Lund, Lund, Sweden). Eleven children (7 boys, age range 2.5-5.8 years) with either a clinical suspicion or a confirmed diagnosis of asthma and 11 healthy adolescents and adults (6 male, age range 13-52 years) were enrolled. With constant output nebulization, the median inhaled mass of budesonide was about 17.6% (range 9.6-21.2%) of the nominal dose (i. e., dose of drug in the respule per label claim) in adolescents and adults, and 18.1% in children (15.7-21.4%). With pulsed nebulization the median inhaled mass increased to 23.4% (22.0-28.1%) in children and to 32.8% (24.8-38.0%) in adolescents and adults (P < 0.001). With breath-synchronized nebulization median inhaled mass increased to 30.1% (21.7-28.1%) in children, but was unchanged (30.8%, 27.0-38. 0%) in adolescents and adults. The mode of nebulization (i.e., constant or breath-synchronized) had a statistically significant effect on the inhaled mass in children and adolescents or adults (P < 0.001). There was a statistically significant difference in inhaled mass between the breath-synchronized and pulsed nebulization in children only (P < 0.05). The results support the use of breath-synchronized but not pulsed nebulization with conventional nebulizers. The results of pulsed nebulization in children warrants further clinical studies.

Reproducibility of home spirometry in children with newly diagnosed asthma.

We evaluated the reproducibility of home spirometry in 110 children aged 5-10 years with newly diagnosed asthma according to the criteria proposed by the American Thoracic Society (level of reproducibility < or = 5%). Flow-volume spirometry was performed in the clinic. Spirometric values were then monitored twice daily at home for 24 days (mean), using a novel device, the Vitalograph(R) Data Storage Spirometer (Vitalograph, Ltd., Buckingham, UK). During this period, the mean (SD) compliance in performing the spirometric tests was 94% (7). In the whole study population, the mean (SD) percentage of reproducible spirometric measurements was 77% (17), although there was wide individual variation (range, 21-100%). In the 5-6-year age group (n = 51), the mean (SD) percentage of reproducible spirometric values was 72.8% (18.6), in the 7-8-year group (n = 38) 77.1% (13.8), and in the 9-10-year group (n = 21) 84. 5% (13.7) analysis of variance, P = 0.02). We conclude that most of the children aged 5-10 years could perform reproducible spirometric tests during home monitoring, although there was wide individual variation. Younger children were less likely to perform reproducible tests than older children. However, a considerable proportion of the measurements (23%) did not meet the criteria of acceptable reproducibility. In order to improve the quality of home monitoring, nonreproducible measurements should be excluded from the calculations.

The conventional ultrasonic nebulizer proved inefficient in nebulizing a suspension.

A study was undertaken to compare the amount of nebulized budesonide suspension and nebulized terbutaline sulphate solution inhaled by healthy adult subjects when conventional jet and ultrasonic nebulizers were used. Ten healthy subjects (5 male; age range, 16-52 years) used two conventional nebulizers: the Spira Elektro 4 jet nebulizer (Respiratory Care Center, Hämeenlinna, Finland) and the Spira Ultra ultrasonic nebulizer (Respiratory Care Center) in a breath-synchronized mode with each drug. The amount of drug inhaled, the inhaled mass, was defined as the amount of drug deposited on a filter between the inspiratory port of the nebulizer and the mouthpiece. The amount of budesonide and terbutaline sulphate was determined by reversed-phase high-performance liquid chromatography. Single-dose respules were used (0.5 mg of budesonide and 5.0 mg of terbutaline sulphate), and nebulization time up to the defined gravimetric output was recorded. The inhaled mass of budesonide varied depending on the nebulizer used, whereas the inhaled mass of terbutaline was unaffected by the choice of nebulizer. The median inhaled mass of budesonide was 31.4% of the nominal dose (i.e., dose of drug in the respule per label claim) with the Spira Elektro 4 and 9.9% with the Spira Ultra, whereas the median inhaled mass of terbutaline was 50% with the Spira Elektro 4 and 52% with the Spira Ultra. It appears that a suspension is generally more difficult to nebulize than a solution and that the budesonide suspension should not be used in conventional ultrasonic nebulizers.

Effects of equipment dead space and pediatric breathing patterns on inhaled mass of nebulized budesonide.

Inhaled mass, the quantity of aerosolized drug actually inhaled by a patient, can be estimated in vitro by using a piston pump and an inhaled mass filter in a manner that simulates in vivo aerosol delivery. For pediatric patients, measurement with an inhaled mass filter with a large equipment dead space (VDEQ) in relation to a small tidal volume (VT) may underestimate the inhaled mass. The present study investigated the impact of VDEQ on the accuracy of in vitro measured inhaled mass of budesonide suspension for nebulization using Spira Module 1 jet nebulizers (Respiratory Care Center, Hämeenlinna, Finland), inhaled mass filters, VDEQs of different sizes, and pediatric breathing patterns. The VDEQ varied between 14 and 108 mL, and the breathing patterns corresponded to a VT between 50 and 500 mL, to breathing frequencies of 40 to 12 per min-1, to a duty cycle of 0.5 for all breathing patterns, and to a nebulization time of 2 minutes. The results showed that the inhaled mass was a function of the VDEQ for each breathing pattern as defined by the inspiratory minute volume (VI). For a large VT, a small VDEQ affected the inhaled mass of budesonide only marginally, but as the VDEQ increased, the measured inhaled mass decreased to the point that for a VDEQ larger than the VT, the inhaled mass was zero. When the inhaled mass was expressed as a function of an effective volume (VEFF) (i.e., VI corrected for VDEQ), the results showed a linear correlation (R2 = 0.921) between the volume of aerosol inhaled through the nebulizer and the inhaled mass of budesonide. The results of the study indicate that VDEQ has a critical effect on the measurement of inhaled mass in vitro for conventional jet nebulizers using pediatric breathing patterns. This means that the in vitro measured inhaled mass of drug can seriously underestimate the in vivo value. When pediatric breathing patterns are used in vitro, a correction of the VT by the VDEQ should be made in order to more accurately reflect the in vivo inhaled mass of drug.

Impact of constant and breath-synchronized nebulization on inhaled mass of nebulized budesonide in infants and children.

The aim of the present study was to compare the output of a breath-synchronized jet nebulizer to a conventional constant output nebulizer over a fixed period of time in terms of inhaled mass of budesonide, i.e., the amount of budesonide deposited on a filter interposed between the nebulizer and the face mask. One hundred and sixty-five asthmatic children (103 boys) were enrolled in this open, randomized, crossover trial. Their age ranged from 6 months to 7.9 years, height from 69 to 132 cm, and weight from 8.2 to 31.3 kg. Their duration of asthma ranged from less than 1 to 7 years. Budesonide suspension, 0.5 mg mL-1, 2 mL, was used. With 5 min of constant output nebulization, the mean inhaled mass of budesonide in percent of the nominal dose was 11.4% in the youngest children and 14.9% in the 7-year-old children. Expressed in percent of the total output of budesonide, i.e., the amount that left the nebulizer as an aerosol, the inhaled mass ranged from 34.6-48.6%. Thus, 51.4-65.4% of the total output was deposited on the expiratory filter. With 5 min of breath-synchronized nebulization, the mean inhaled mass ranged from 10.5-14.9% of the nominal dose. For the youngest patients less than 3-4 years of age, it was approximately 80-90% of the total output. For the older patients the inhaled mass was approximately 95% of the total output, i.e., only small amounts of budesonide were deposited on the expiratory filter. For both modes of nebulization the between-subject variation in inhaled mass was large: up to 6-fold in the young children and 3-4-fold in the older ones. The results of the present study showed that the inhaled mass of budesonide was significantly age-dependent with both modes of nebulization, i.e., the inhaled mass was less in younger children. Breath-synchronized nebulization resulted in reduced waste of drug during expiration.

Drug delivery from the Turbuhaler and Nebuhaler pressurized metered dose inhaler to various age groups of children with asthma.

A total of 198 children aged 3 to 15 years inhaled a single dose of 200 micrograms budesonide from a Nebuhaler pressurized metered dose inhaler (pMDI) and a Turbuhaler dry powder inhaler in a randomized crossover study. The budesonide dose delivered to a patient was assessed by measuring the amount of drug deposited on a filter inserted between the inhaler outlet and the patient's mouth. The dose of budesonide deposited on the filter and the estimated dose of particles with a mass median aerodynamic diameter (MMAD) of 5 microns or less after inhalation from the Turbuhaler were both approximately twice the values inhaled from the pMDI Nebuhaler in children less than 5 years of age (P < 0.01). The variation in the dose delivered to the patient was similar for the two inhalers in children over 5 years old. In 3- to 4-year-old children, dose delivery to the patient was higher and/or more consistent from the pMDI Nebuhaler than from the Turbuhaler. Filter dose after Turbuhaler treatment varied significantly from peak inspiratory flow rate through the Turbuhaler (PIFTbh) (P < 0.01). The percentage of children producing a PIFTbh greater than 50 L/min decreased with age (89%, 45%, and 14% in 5-, 4-, and 3-year-old children, respectively). It is concluded that drug delivery to a child with asthma varies with age and inhalation device. Further studies are needed to assess the clinical importance of this finding.

Metered dose inhaler add-on devices: is the inhaled mass of drug dependent on the size of the infant?

Limited cooperation and low tidal volumes in infants make aerosol therapy difficult. We measured the amount of drug delivered from two baby spacer devices especially developed for use in infants. Designed as a randomized crossover study, aerolized budesonide from a pressurized metered dose inhaler (pMDI) was collected in the inspiratory filter interposed between the face mask and the spacer in 13 infants aged from 2 to 19 months old. The study was performed in connection with pulmonary function testing with a plethysmograph, and the children were sedated with cloral hydrate. Two small-volume baby spacer devices were used: a Babyhaler spacer (GlaxoWellcome, Hertfordshire, UK) made of polycarbonate with a volume of 350 mL and a built-in dead space of 40 mL and a NebuChamber spacer (AstraZeneca, Lund, Sweden) made of stainless steel with a volume of 250 mL and no dead space. Budesonide delivery from the NebuChamber was significantly higher than from the Babyhaler: 38.2% (range, 28.3%-47.5%) of the nominal dose versus 12% (range, 3.3%-21.25%) of the nominal dose of 400 micrograms of budesonide (P = 0.002). The inhaled mass of budesonide from the Babyhaler correlated significantly with skin surface area (r = 0.68, P = 0.018), weight (r = 0.66, P = 0.019), height (r = 0.69; P = 0.017), tidal volume (r = 0.82; P = 0.004), and minute volume (r = 0.67; P = 0.019). No correlations were found between these variables and the inhaled mass of budesonide from the NebuChamber. The results indicate that the design of the NebuChamber spacer affords stable drug delivery in infants and that a large variability in the inhaled mass of drug may be found when infants are inhaling from different baby spacers.

Comparative study of budesonide as a nebulized suspension vs pressurized metered-dose inhaler in adult asthmatics.

The study objective was to compare the effect of budesonide administered as a nebulized suspension as compared to a spray with a spacer in adult asthmatics. In a double-blind, double-dummy crossover study, 26 adult patients with moderately severe unstable asthma were randomized to three 4-week treatment periods with budesonide 0.8 mg b.i.d. administered by a pressurized metered-dose inhaler (pMDI) with spacer (Nebuhaler) and budesonide 1 mg and 4 mg b.i.d. administered by a Pari Inhalier Boy jet nebulizer. The nebulizer was activated only during inspiration. The total mass output was similar from the two devices but their fraction of small particles differed by a factor of 2 in favour of pMDI. Effect was evaluated from daily home measurements of peak expiratory flow (PEF), need of beta 2-agonist and symptom scores. Plasma cortisol and budesonide levels were measured in a subgroup of 10 patients. A consistent trend showed the nebulizer treatment to be at least as efficient as the pMDI plus spacer treatment. In actual fact, the apparent order of effect was: 4 mg nebulized suspension treatment > or = 1 mg nebulized suspension treatment > or = 0.8 mg pMDI with spacer treatment. Plasma budesonide and plasma cortisol also exhibited dose-related levels independent of device. The adverse effects reported appeared to be related to the dose rather than delivery device. Accordingly, the effect was related to total mass output, rather than to the small particle fraction of the budesonide aerosol. These results attest to the efficiency of jet-nebulized budesonide suspension, and indicate nebulized budesonide to be equipotent to standard budesonide therapy delivered by pMDI with Nebuhaler, provided nebulization is synchronized with inspiration and no loss of aerosol occurs during expiration.

Effect of 1 year daily treatment with 400 microg budesonide (Pulmicort Turbuhaler) in newly diagnosed asthmatics.

The aim of this study was to investigate whether treatment with a low daily dose of 400 microg inhaled budesonide (Pulmicort Turbuhaler) in newly diagnosed asthmatics could influence the course of asthma. Seventy five adult patients, mostly with mild asthma, diagnosed during the previous year and bronchial hyperresponsiveness, participated in a double-blind, randomized, parallel-group multicentre study. They were treated with budesonide 200 microg b.i.d. or placebo, delivered via Turbuhaler for 12 months and followed-up for another 6 months without inhaled steroid treatment. Airway function, symptom scores, reactivity to histamine and inflammatory indices in blood were assessed. The mean increase in morning peak expiratory flow (PEF) was 28 L x min(-1) after budesonide treatment compared with no increase in the placebo group (p=0.011). The provocative dose of histamine causing a 20% fall in forced expiratory volume in one second (PD20) (geometric mean) increased in the budesonide group by approximately two doubling dose steps, but not in the placebo group (p=0.0003). The difference between groups with regard to improvement in asthma symptom scores and inflammatory indices did not reach statistical significance. During the 6 month follow-up, the PEF values of the patients who had previously been treated with budesonide decreased by 18 L x min(-1) while the PD20 decreased by approximately one doubling dose step. In conclusion, early treatment with a low dose of budesonide improves airway function and decreases bronchial responsiveness, but the improvements are short-lasting without continued treatment.