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(Chest. 2003;124:790-794.)
© 2003 American College of Chest Physicians

A Randomized Controlled Trial of Inhaled Flunisolide in the Management of Acute Asthma in Children*

Albert K. Nakanishi, MD; Ann K. Klasner, MD and Bruce K. Rubin, MD, FCCP

* From the Department of Pediatrics (Dr. Nakanishi), St. Louis University School of Medicine, St. Louis, MO; Department of Pediatrics (Dr. Klasner), University of Alabama-Birmingham, Birmingham, AL; and Department of Pediatrics (Dr. Rubin), Wake Forest University School of Medicine, Winston-Salem, NC.

Correspondence to: Albert K. Nakanishi, MD, Associate Professor of Pediatrics, St. Louis University School of Medicine, Cardinal Glennon Children’s Hospital, 1465 S. Grand Blvd, St. Louis, MO 63119; e-mail: Nakanimk{at}slu.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Inhaled corticosteroids (ICS) may provide benefit in the therapy of acute asthma. The purpose of this study was to test the hypothesis that ICS are as effective as oral corticosteroids (OCS) in the management of acute childhood asthma.

Methods: A randomized, masked, placebo-controlled study was conducted in children aged 6 to 16 years seeking emergent care for an acute exacerbation of asthma. Patients were randomized into one of two groups: group 1 (OCS), oral prednisone, 2 mg/kg (maximum of 60 mg/d) for 7 days, and placebo pressurized metered-dose inhaler with valved holding chamber, four inhalations bid; and group 2 (ICS), flunisolide, four inhalations (1 mg) bid for 7 days, and daily placebo tablets. Spirometry (FEV1) was performed at baseline, day 3, and day 7 of the study. A symptom diary and twice-daily peak expiratory flow were recorded.

Results: A total of 58 subjects receiving ICS (n = 27) or OCS (n = 28) were enrolled. Baseline asthma severity, race, gender, and age were balanced between the two groups. {chi}2 showed no significant difference in symptom severity between the two groups at any time during the study. FEV1 percentage of predicted was lower in the ICS group on day 3 (65% vs 78%, p = 0.03) and on day 7 (77% vs 95%, p = 0.002).

Conclusion: ICS were found to be useful in the management of acute asthma in children; however, spirometry data suggested a more rapid resolution of asthma with OCS.

Key Words: acute childhood asthma • inhaled corticosteroids • metered-dose inhaler • oral corticosteroids • randomized controlled study • spirometry


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Corticosteroids are the most commonly used anti-inflammatory medications for the treatment of acute exacerbations of asthma in adults and children.1 2 3 4 5 6 Corticosteroids block the generation of inflammatory mediators, reduce pulmonary vascular leakage, down-regulate airway mucus secretion, and increase the number and affinity of airway ß-adrenergic receptors.7 8 9 10 11

Morbidity is reduced when systemic corticosteroids are started early in the treatment of acute asthma. Clinical trials have demonstrated that oral, IM, and IV corticosteroids administered in the emergency department (ED) can reduce the frequency of hospital admission, improve pulmonary function, and reduce the relapse rate after discharge from the ED.12 13 14 15 16 17 18 Nearly all studies have confirmed that systemically administered corticosteroids provide significant therapeutic benefit when treating acute asthma; however, not all children with acute asthma tolerate systemically administered corticosteroids. IV or IM administration can cause pain with administration, and oral forms of corticosteroids are associated with an unpleasant taste and can lead to vomiting or poor adherence.18 Concerns regarding side effects of systemic corticosteroids may also limit their use.19 20 21

Although inhaled corticosteroids (ICS) are highly effective therapy for the management of chronic asthma,1 there is concern that corticosteroids administered by aerosol may not provide the same rapid and effective therapy as oral corticosteroids (OCS) when used for rescue therapy in the acute exacerbation of childhood asthma. We therefore undertook a study to test the hypothesis that ICS are effective in the management of acute asthma exacerbations in children.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
A randomized, masked, placebo-controlled, parallel-group study was conducted in 55 children aged 6 to 16 years seeking care for an acute exacerbation of asthma. Patients were excluded from enrollment if they had underlying lung disease such as cystic fibrosis or bronchopulmonary dysplasia. Patients were also excluded if they required hospital admission or had an initial FEV1 <25% or > 80% of predicted.

Baseline spirometry, peak expiratory flow (PEF), heart rate, respiratory rate, pulse oximetry, height, and weight were recorded from eligible patients. Patients then received 0.15 mg/kg (up to 5 mg) of albuterol and at the discretion of the treating physician; ipratropium bromide, 0.25 mg, was also administered to the patient by jet nebulization (Whisper Jet; Marquest Medical Products; Englewood, CO) using a fill volume of 4 mL and oxygen flow of 8 L/min. Bronchodilator therapy was repeated until the PEF was > 70% of predicted, at which time informed assent and/or consent was obtained, and patients were randomized into one of two experimental treatment groups.

One group (OCS group) received oral prednisone, 2 mg/kg (maximum of 60 mg/d) for 7 days, and placebo pressurized metered-dose inhaler (pMDI), four inhalations bid. The second group (ICS group) received flunisolide with a valved holding chamber (VHC) [Aerochamber; Monaghan Medical; Plattsburg, NY], four inhalations (1 mg) bid for 7 days and daily placebo tablets. Patients were instructed in the use of the pMDI and VHC. Forest Laboratories (New York, NY) prepared placebo inhalers, tablets, and the patient randomization sequence. Patients unable to swallow the tablets were instructed to crush the tablets into a suitable sweetened vehicle for oral administration. The pMDI canisters were labeled similarly and were indistinguishable with regard to taste. The researchers were blinded to the randomization codes throughout the study.

On discharge, albuterol was administered on an as-needed basis for PEF of < 80% predicted. Each patient was given a TruZone (Monaghan Medical) peak flowmeter and instructed in its use. Asthma diary cards were also provided with instructions for recording symptoms and twice-daily PEF measurements. Patients returned for follow-up spirometry on day 3 and day 7 of the study period. FEV1 was measured using a portable spirometer (MultiSPIRO-SX; MultiSPIRO; Irvine, CA). The best of three maximal expiratory curves generated by the patient were recorded in concordance with the criteria established by the American Thoracic Society.22 The study concluded on day 7 with the return of asthma diary cards and study drugs. The Institutional Review Board approved this study.

Data Analysis
Data were analyzed using a Mann-Whitney U test for between-group comparisons of percentage of predicted FEV1, the primary outcome variable. Secondary outcome variables included symptom score, initial vital signs and oximetry, side effects, recurrence rate for acute asthma symptoms, and daily PEF. Student t test was used to compare means of normally distributed continuous variables. Nominal variables were analyzed by contingency tables. The sample size calculations used FEV1 as the primary outcome variable. We used data from previous studies, where FEV1 was measured in children with acute asthma and changes in pulmonary function in a placebo and treatment group.23 Assuming an {alpha} of 0.05 for a one-tailed test and a ß of 0.05, we calculated a sample size of 44 patients would have a 95% power to detect a 20% difference in FEV1 or an 80% power to detect a 15% difference.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A total of 58 subjects were enrolled, of whom 35 were male and 49 were African American. Baseline asthma severity, race, gender, and age were balanced between the two treatment groups (Table 1 ). Twelve patients (seven patients in the ICS group) were enrolled who were routinely receiving maintenance doses of ICS. Prior use of ICS did not alter the study results.


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  		Table 1.. Baseline Data*

 
Contingency analysis showed no significant difference in symptom severity between the two groups at any time during the study. Similarly, morning PEF showed no significant difference between groups on any day of the study period when assessed by Mann-Whitney U test (Fig 1 ). The FEV1 percentage of predicted for the ICS group was lower on day 3 (65% vs 78% for OCS, p = 0.03) and on day 7 (77% vs 95%, p = 0.002) [Table 2 ]. Both groups continued to improve over the 7-day study period, with the most improvement in those patients receiving OCS (Fig 2 ).



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  		Figure 1.. Morning (AM) PEF vs time.

 

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  		Table 2.. Spirometry Results*

 


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  		Figure 2.. FEV1 percentage of predicted vs time.

 
Reported side effects were minimal. One patient stopped the oral placebo pills due to taste, and two patients stopped the inhaler for similar reasons, one from each study group. The asthma diary information was not completed for eight patients in the ICS group and six patients in the OCS group. Two patients did not undergo follow-up in the ICS group. One patient in the ICS group required additional corticosteroids after the 7-day study period, and one patient in the OCS group required hospital admission for asthma within 24 h following ED therapy and enrollment.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Earlier studies suggest that high-dose ICS are as effective as OCS in treating acute asthma in adults24 25 and children,26 27 28 29 although data regarding pediatric asthma were not as clear.30 In a study comparing budesonide, 1,600 µg/d, by Turbuhaler (Astra; Lund, Sweden), or oral prednisone, 2 mg/kg, therapy in children with acute asthma, there was an earlier response in those treated with budesonide as measured by pulmonary index scores and PEF. They also found serum cortisol levels were lower in those treated with oral prednisone, suggesting adrenal suppression.26 In two other studies, nebulized budesonide was compared with oral prednisone in children with acute asthma in the ED,27 or in children admitted to hospital with asthma.28 Both studies favored budesonide with regards to oxygen saturation, respiratory rate, and symptom scores. In an early study comparing nebulized dexamethasone and oral prednisone, Scarfone et al29 found equivalent efficacy in children with acute asthma.

Differing from these studies, Schuh and coworkers30 found a higher rate of hospital admission for children receiving inhaled low-dose fluticasone compared with oral prednisone (31% vs 10%) during a 4-h observation period in the ED. The authors suggested that this might have been related to poor delivery of the aerosolized fluticasone in inflamed and narrowed airways. Unlike the present study, the dose of inhaled steroids administered by Schuh and coworkers30 was lower, and the primary outcome was hospital admission, while the patients that we studied were all discharged from the ED and were monitored over a 7-day study period following the stabilization of the initial acute episode. Although we found no clinical difference between the two study groups, there was a significant difference in spirometry with greater improvement in the OCS group (Fig 2) . This may be explained by the fact that the ICS group had a 5% lower FEV1 to begin with (Table 2) .

Children with acute asthma are tachypneic with high inspiratory flow and low tidal volume, factors limiting aerosol deposition to the airways.31 The dose of inhaled flunisolide was arbitrarily doubled for this study from the dosage recommended for chronic asthma control to address these factors limiting aerosol deposition during an acute asthma exacerbation. Even so, there potentially could be a 30-fold difference in dosage between the oral and inhaled corticosteroids in the two study groups, which may have contributed to the difference in response rather than the method of administration.

Flunisolide has moderate potency relative to dexamethasone, with extensive first-pass metabolism in the liver, minimizing any systemic absorption.32 We did not detect any short-term side effects associated with the use of ICS. Accessory devices (ie, VHC) can increase aerosol deposition, and studies31 33 34 have demonstrated approximately 11 to 20% of a dose from a pMDI with VHC reaches the lower airways. VHC reduces the oral and pharyngeal deposition of ICS and side effects.1 31 We did not measure serum cortisol level during the study period, although there is evidence that even short courses of OCS can depress the hypothalamic-pituitary axis.26

Although we examined the study participants twice over the 7-day study period, adherence with taking the study drugs was not directly assessed. Some patients failed to return study drug containers, and some did not fully complete asthma diaries. The self-reporting of patient symptoms and recording of PEF are notoriously inaccurate.35 36 By having frequent follow-up and spirometry data during the study period, we hoped to minimize some of these errors in reporting.

In summary, topically administered corticosteroids may reduce airway mucosal swelling and inflammation, since the amount of systemically absorbed corticosteroids for the most part, appears to be low.24 32 Based on clinical examination and patient interview at day 7, we found no clinical difference in the response to ICS or OCS, and both groups continued to improve over the 7-day study period. However, spirometry data suggested a more rapid resolution of asthma in the patients receiving OCS.


   Footnotes
 
Abbreviations: ED = emergency department; ICS = inhaled corticosteroids; OCS = oral corticosteroids; PEF = peak expiratory flow; pMDI = pressurized metered-dose inhaler; VHC = valved holding chamber

Presented at the American Academy of Pediatrics 2000 Annual Meeting, Chicago, IL; October 27–31, 2000.

Dr. Rubin is a consultant to Forest Laboratories and Monaghan Medical.

Funded by a grant from Forest Laboratories.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions{at}chestnet.org).

Received for publication October 10, 2002. Accepted for publication February 11, 2003.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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