INTRODUCTION

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₂-Agonist is the primary reliever treatment of bronchial asthma in all age groups. Young asthmatic children are especially in need of bronchodilation and bronchoprotection of long duration because intermittent treatment with short-acting ₂-agonists may be insufficient as the treatment decision and drug delivery are dependent on a trained caretaker, who often has to hand over the observation and care of the child to others for large parts of the day. Therefore, long-acting ₂-agonists would be of significant clinical benefit for young asthmatic children. Inhaled formoterol has a rapid onset of action within a few minutes after inhalation, a maximal effect within 30 min, and sustained, significant bronchodilation and bronchoprotection over 12 h (1). Side effects from a number of standard doses of formoterol were reported to be similar to those of the same number of standard doses of short-acting ₂-agonists in adults (7).

Inhaled aerosol is the preferred route for reliever treatment because of the rapid onset of action and minimized systemic effects. However, aerosol treatment of young children is limited by their inability of reliable cooperation. Therefore, young asthmatic children are often prescribed aerosol treatment from nebulizers or from pressurized metered-dose inhaler (pMDI) and a spacer (8). The nebulizer is hampered mainly from inaccurate drug delivery and price, whereas the combination of pMDI and spacer is disadvantaged from pMDI irritants and propellants. A new concept recently devised the mechanical actuation of a DPI into a spacer for subsequent inhalation by young children without need for active cooperation. This device provides a stable aerosol of fine particles without additives for accurate aerosol treatment (9).

Lung function measurements requiring active cooperation are not feasible in children younger than 6 yr of age. Measurements during tidal breathing in nonsedated preschool children are better accepted (10) and we have previously demonstrated that use of whole body plethysmography (measuring specific airway resistance [sRaw]) in the assessment of the bronchoconstrictor response to cold, dry air (11) and bronchodilator responsiveness to short-acting ₂-agonists (12) is feasible and a helpful tool in diagnosing asthma in young children. Furthermore, we recently demonstrated the usefulness of these tools in clinical studies of antiasthma medication in asthmatic young children (13, 14).

The aim of this study was to delineate the time profile and magnitude of the bronchodilatory and bronchoprotective effect of formoterol dry powder 9 µg inhaled from a mechanically actuated DPI using a spacer in asthmatic young children.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Subjects

Children ranging in age from 2 to 5 yr, with an asthma diagnosis based on typical asthma symptoms, symptom relief from inhaled corticosteroids or inhaled ₂-agonist, and relapse during interruption of such treatment were eligible for the study. No signs of acute asthmatic symptoms were present on the study days. Current medication for asthma was maintained unchanged during the last month before the first visit. Short- and long-acting ₂-agonists were withheld at least 8 and 24 h, respectively. Leukotriene receptor antagonists were stopped 1 wk before screening. Children were invited into the study if the response to cold air challenge (CACh) was considered positive, as defined subsequently.

sRaw

Measurement of sRaw was performed using a constant-volume whole body plethysmograph (Master Screen Body, version 4.34; E. Jaeger GmbH, Würzburg, Germany). Measurements were done during tidal breathing in a face mask (Astratech No 2; Astra Tech, Taastrup, Denmark) fitted with a flexible, noncompressible mouthpiece securing support of cheeks and stable access to the airways through the mouth. sRaw was calculated as the relationship between simultaneous variations of respiratory flow and variations of pressure in the plethysmograph based on the maximal pressure changes during inspiration and expiration (10, 15, 16).

CACh Test

CACh was carried out as a single-step 4-min isocapnic hyperventilation test. Cold, dry air was generated by a Respiratory Heat Exchange System (RHES; E. Jaeger GmbH) delivering 15° C cold, dry air mixed with 5% CO₂. Hyperventilation rate was aimed at 1 L/min/kg body weight. Ventilation was measured at the exhalation valve by a pneumotachograph (11). Mean of duplicate measurements of sRaw before CACh defined the baseline. Mean of duplicate measurements 4 min after the end of a challenge defined the postchallenge sRaw. The same observer performed all measurements.

Mechanically Actuated DPI with Spacer

The DPI (Turbohaler; AstraZeneca, Lund, Sweden) is activated mechanically into the spacer by generation of a partial vacuum in the spacer on release of a spring-driven piston. The spacer has a volume of 275 ml and is nonelectrostatic. The child inhales the aerosol from the spacer by tidal breathing via face mask or mouthpiece. This device has previously been described in detail (9).

Study Design

The study was a single center, randomized, double-blind, placebo-controlled, crossover, and three-period study with a washout period of minimum 48 h between treatments. The randomization was computer-generated. Treatments were given as formoterol Turbohaler 4.5 µg two actuations, salbutamol Turbohaler 100 µg two actuations, or placebo Turbohaler two actuations between 8:00 and 9:00 A.M. All trial medication was delivered by the mechanically actuated DPI via spacer. The child inhaled 10 times at tidal breathing from the spacer after each actuation. sRaw was measured before, 3, 5, 8, and 15 min and 4 and 8 h after inhalation of trial medication. CACh was performed after 15 min and after 4 and 8 h.

The study was approved by the local ethics committee (KF-02-100/ 99) and the National Health Authorities (2612-1146). Written informed consent was obtained from parents.

Data Analysis

All children completing all study days were included in the analyses of treatment effects based on the intention-to-treat principle. The blinded code was broken after clean file had been declared and data files had been locked in the computer. Response to CACh was quantified as percentage increase from baseline value. A positive response to CACh was defined as an increase in sRaw of  20%. Percentage protection was calculated as 100 · (CACh_Plac  CACh_Active) / CACh_Plac, where CACh_Plac and CACh_Active designate the mean percentage increase in sRaw after CACh on placebo and formoterol or salbutamol treatment, respectively.

We estimated that a minimal relevant difference in maximal percentage change in sRaw of 20% between treatment groups would be detected with a power of 95%, with 12 patients in a crossover study. Analyses of treatment effects were done by two-tailed paired t tests with 0.05 as level of significance. Central tendency was expressed by the arithmetic mean and 95% confidence interval (95% CI) or range. Baseline data were compared between treatments and with reference values calculated as percentage of predicted according to height (17).

	RESULTS

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Fifteen children were screened for this study, but two 2-yr-olds were not able to perform satisfactory plethysmographic measurements and one 3-yr-old did not meet the criteria of a change of > 20% in sRaw after CACh. Baseline characteristics at screening visit of the 12 patients completing the study are presented in Table 1. The mean age was 4.6 yr ranging from 2 to 5 yr. The mean duration of asthma disease was 38 mo (range, 16 to 72). Seven had a first-degree relative with atopic disease, eight had at least one clinically relevant positive skin prick or specific serum-IgE test to the 10 inhalant allergens most common in Scandinavia, and six had atopic dermatitis or rhinitis, or both. Seven patients were in current treatment with inhaled budesonide in a mean daily dose of 400 µg and short-acting ₂-agonist as required, both delivered through pMDI and Nebuchamber spacer (AstraZeneca, Albertslund, Denmark). The rest of the patients received treatment with short-acting ₂-agonist as required. Seven patients were known to have bronchial hyperresponsiveness to CACh from previous studies (11, 13, 14) or routine tests in the clinic.

Baseline sRaw at the placebo day was 132% (95% CI: 112 to 152) of predicted lung function (17), i.e., the children presented a significantly increased airway resistance at baseline (Table 1). This baseline lung function did not change between placebo, salbutamol, and formoterol treatment days (Figure 1). At the screening visit the mean maximal response to CACh was 50% (95% CI: 36 to 63).

View larger version (10K): [in this window] [in a new window]   Figure 1.   Mean sRaw curves in absolute values predose (baseline) and through 8 h after administration of placebo, salbutamol, and formoterol single dose from a mechanically actuated DPI using a spacer. Diamond = placebo; square = salbutamol; triangle = formoterol.

sRaw of the asthmatic young children improved significantly after inhalation of both salbutamol (p < 0.05) and formoterol (p = 0.003) without difference between treatments (p = 0.25) (Figure 1). This effect was apparent at the first measurement 3 min postdose. The significant bronchodilatory effect of formoterol was sustained through 8 h, whereas the bronchodilatory effect from salbutamol was no longer significant at the 4-h time point.

Figure 2 shows the mean maximal percentage change from pre-CACh to post-CACh level. Formoterol provided sustained and significant bronchoprotection against cold, dry air- induced bronchoconstriction for at least 8 h compared with placebo (p = 0.0006 at 15 min, p = 0.02 at 4 h, and p = 0.0002 at 8 h). Formoterol provided significantly better bronchoprotection than salbutamol from 4 h onward (p = 0.002 at 4 h and p = 0.0005 at 8 h). Salbutamol provided no significant protection at 4 and 8 h. Calculations of the percentage protection from each treatment relative to placebo at each time point are shown in Table 2. Formoterol demonstrated clinically relevant protection rates of approximately 80% at all time points; salbutamol only exceeded 50% protection at 15 min postdose. No adverse events were seen or reported during the study period.

View larger version (15K): [in this window] [in a new window]   Figure 2.   Maximal percent increase in sRaw (expressed as percentage of baseline) after CACh at 15 min, 4 h, and 8 h after single dose of placebo (- - - - -), salbutamol (- ·· -), and formoterol (). Mean and 95% CI are shown.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

This is the first report on the effect of long-acting ₂-agonist on lung function in young asthmatic children. It is also the first report on the clinical effectivity of a new device based on the principle of mechanical actuation of DPI into a spacer, which aims at aerosol treatment of patients unable to cooperate with active inhalation maneuvers (9). Formoterol Turbohaler 9 µg dry powder, delivered as inhalations from this mechanical spacer, offered a rapid and sustained bronchodilation and bronchoprotection for at least 8 h compared with placebo. Salbutamol provided less than 4 h of bronchodilation and bronchoprotection.

The combination of a DPI and an automatic spacer offers many advantages. Like the combination of spacer and pMDI this device presents a standing cloud of aerosol without requirement of coordination or effort and with few coarse particles. Furthermore, the automatic spacer delivers no harmful additives, has high dose-to-dose repeatability, a high yield of drug, and a long availability of aerosol. The particles are characterized by a mass median aerodynamic diameter of 2.8 µm with a geometric standard deviation of 1.8 µm. The aerosol is airborne over a long period with the slow fall-out. The half-life of the spontaneous fall-out of the fine particle aerosol is 82 s (9). The present study attests to the fact that this device delivers clinically effective doses to the lungs of young children 2 to 5 yr of age.

₂-Agonists remain indispensable as reliever therapy for the treatment of bronchial asthma in all age groups during exacerbations. The fast onset of action shown in this study of young children with statistically significant bronchodilation within 3 min postdosing similar to that of salbutamol, suggests a potential role of formoterol as rescue medication in this age group, as previously suggested (6). The long-acting effect of formoterol demonstrated in the present study is in keeping with our previous results in similar comparative placebo-controlled studies of bronchodilatory and bronchoprotective effect of formoterol and salbutamol in schoolchildren (4, 5).

Young asthmatic children are especially in need of bronchodilation and bronchoprotection of long duration because intermittent treatment with short-acting ₂-agonists is often insufficient as the treatment decision and drug delivery are dependent on a trained caretaker, in most cases the mother, who often has to hand over the observation and care of the child to others for large parts of the day. The duration of bronchodilation and bronchoprotection of 8 h is clinically relevant as most of the children would be satisfactorily protected during the time spent in day care. Therefore, long-acting ₂-agonists "as needed" would be of significant clinical benefit for young asthmatic children. During symptomatic periods, the parents could give the child one treatment in the morning to ensure effective symptomatic relief throughout the day.

In keeping with previous clinical studies of formoterol in schoolchildren (4), we did not observe any adverse events in this study. In studies in schoolchildren, formoterol was associated with the occurrence of minimal side effects; in fact the most commonly reported adverse events were disease-related (6). In adults the systemic effects have the same short duration with formoterol as with the short-acting ₂-agonists. A high number of standard dose inhalations of formoterol elicited less systemic response than the same high number of standard dose inhalations of terbutaline (7). In children, a single-dose study found no difference in systemic side effects between high-dose formoterol (48 to 78 µg) and salbutamol (18). This study demonstrated good tolerance of formoterol, and has shown that, in contrast to its bronchodilating effect, the systemic effects of formoterol are short-lasting and similar to those observed with short-acting ₂-agonists.

In conclusion, formoterol administered as dry powder Turbohaler 9 µg single dose, delivered from a DPI by mechanical actuation using a spacer, provided sustained bronchodilation and clinically significant bronchoprotection against bronchoconstriction for at least 8 h after medication in 2- to 5-yr-old asthmatic children. Furthermore, this study suggests that administration of dry-powder formulations by mechanical actuation using a spacer is an effective and convenient method of aerosol treatment of asthma in young children.