A randomized clinical trial on inhaled ciclesonide for managing acute asthma in the emergency room

ABSTRACT BACKGROUND: Use of inhaled corticosteroids for managing acute asthma exacerbations has been tested since the 1990s. OBJECTIVE: To compare high doses of inhaled ciclesonide with systemic hydrocortisone for managing acute asthma exacerbations in the emergency department. DESIGN AND SETTING: Double-blind, randomized clinical trial in the public healthcare system of the city of São Paulo. METHODS: Fifty-eight patients with moderate or severe asthma with peak flow < 50% of predicted were randomized into two groups. Over the course of four hours, one group received 1440 mcg of inhaled ciclesonide plus hydrocortisone-identical placebo (ciclesonide + placebo), while the other received 500 mg of intravenous hydrocortisone plus ciclesonide-identical placebo (hydrocortisone + placebo). Both groups received short-acting bronchodilators (fenoterol hydrobromide and ipratropium bromide). The research protocol included spirometry, clinical evaluation, vital signs and electrocardiogram monitoring. Data were obtained at 30 (baseline), 60, 90, 120, 180, and 240 minutes. We compared data from baseline to hour 4, between and within groups. RESULTS: Overall, 31 patients received ciclesonide + placebo and 27 received hydrocortisone + placebo. Inhaled ciclesonide was as effective as intravenous hydrocortisone for improving clinical parameters (Borg-scored dyspnea, P = 0.95; sternocleidomastoid muscle use, P = 0.55; wheezing, P = 0.55; respiratory effort, P = 0.95); and spirometric parameters (forced vital capacity, P = 0.50; forced expiratory volume in the first second, P = 0.83; peak expiratory flow, P = 0.51). CONCLUSIONS: Inhaled ciclesonide was not inferior to systemic hydrocortisone for managing acute asthma exacerbations, and it improved both clinical and spirometric parameters. TRIAL REGISTRATION: RBR-6XWC26 - Registro Brasileiro de Ensaios Clínicos (http://www.ensaiosclinicos.gov.br/rg/RBR-6xwc26/).

expression of beta-adrenoceptors in bronchial smooth muscle tissue. This effect is also shared by inhaled corticosteroids and begins four to six hours after administration, 13 although some studies have shown that systemic corticosteroids administered to severely ill patients up to one hour after emergency department admission yields clinical benefits, such as reduced hospitalization rate and shorter length of emergency department stays. 14,15 Data from double-blind randomized controlled trials have suggested that, compared with systemic corticosteroids, inhaled corticosteroids can decrease admission rates and allow earlier discharge from the emergency department. Peak flow levels and forced expiratory volume in the first second (FEV1) also rise more quickly in patients who are given inhaled corticosteroids. [16][17][18][19] OBJECTIVE To the best of our knowledge, this was the first double-blind randomized clinical trial with the objective of comparing high doses of inhaled ciclesonide with use of injectable hydrocortisone for managing acute asthma in emergency settings. This trial was justified by the expected potential for fewer side effects with inhaled ciclesonide, the supposed benefit of its rapid onset of action and the need for more inhaled drugs to be available for clinicians dealing with asthma exacerbation in the emergency department.

Population and setting
We studied patients with asthma aged 13 years or older, of both sexes, in the city of São Paulo, Brazil. Patients were recruited from the emergency department of Hospital São Paulo (a teaching hospital that is part of the Universidade Federal de São Paulo [UNIFESP]) and from two freestanding public urgent care centers affiliated with the hospital: Assistência Médica Ambulatorial (AMA) Santa Cruz and AMA Sacomã.
We included patients with a previous diagnosis of asthma (dyspnea, coughing, wheezing and chest tightness, associated with allergen exposure or cold air) 20

Study design
This was a double-blind, placebo-controlled, randomized clinical trial that was designed to compare the efficacy of inhaled ciclesonide versus intravenous hydrocortisone for managing moderate or severe acute asthma in an emergency department setting.

Blinding
Both blinding and randomization were done centrally at the Neuro-Sono Sleep Center, São Paulo, Brazil. Blinding of active ingredients and their respective placebos was achieved by random allocation of four letters (A, B, C and D) to each of the following products: hydrocortisone, ciclesonide, hydrocortisone-identical placebo and ciclesonide-identical placebo. After random allocation of letters to designate each product, we defined two product pairs: Inhaled Active Ingredient + Intravenous Placebo; and Intravenous Active Ingredient + Inhaled Placebo. This was done in random combinations that enhanced the safety of blinding.
Both the intravenous placebo and the inhaled placebo were identical to their active counterparts.
Information about the intervention that each patient randomized to the study would receive was distributed in opaque numbered envelopes, which were only opened at the time of use. The nursing staff prepared the medications for administration as instructed in the numbered envelopes. The staff who prepared the medications, the providers who administered them and all researchers involved were blinded to the active pharmaceutical ingredients of interest.

Randomization
Patients included in the sample were recorded consecutively in a logbook and were assigned a serial number.
The 58 patients were divided into two groups: study (ciclesonide) and control (hydrocortisone), in accordance with two computer-generated random number tables. Each table contained an ascending sequence of numbers. Patients were allocated to one or the other according to the serial number attributed at the time of enrollment, which ensured that neither staff nor patients were aware of the intervention to which each patient would be allocated.

Ciclesonide group
Patients received ciclesonide at a dose of 160 mcg/puff. The first dose was administered five minutes after inclusion in the trial, and

Hydrocortisone group
Patients in this group received 500 mg of hydrocortisone intravenously and ciclesonide-identical placebo at 5, 20 and 40 minutes.

Both groups
Both groups received short-acting bronchodilators (fenoterol hydrobromide and ipratropium bromide) at 0, 10 and 30 minutes.

Measurements
We used the spirometric variables FEV1 and peak expiratory flow (PEF) as primary outcome measurements, along with the clinical variables of dyspnea, wheezing and accessory muscle use during breathing (as assessed through observation of the sternocleidomastoid muscle). As secondary outcomes, we evaluated the heart rate, respiratory rate, blood pressure and pulse oximetry.
These parameters were measured every 30 minutes from the time of patient admission until the second hour and every 60 minutes thereafter until the fourth hour in the emergency department, thus making a total of six measurements. In this manner, we ensured rigorous monitoring throughout the patient observation period. We analyzed all six measurements, and no statistical difference was observed in comparisons of each paired time point (Table 1). For the purposes of this study, we analyzed and showed data from 30 minutes (baseline) and from the fourth hour, as we felt that these assessments were sufficient to represent the patients' course, among the six measurements obtained.

Procedures
The emergency room nurse applied the Manchester triage system and measured oxygen saturation, blood pressure and breathing pattern. The emergency room physician then confirmed the diagnosis of asthma exacerbation and notified the investigators, who performed an initial assessment by measuring peak flow and explained the study to the patient. Patients with a peak flow less than 50% of the predicted flow were invited to participate in the study (Figure 1), as the sample was designed to include only severe patients.
Once the patient had been included, the investigators worked with the emergency department staff to provide all the necessary care and perform the measurements required for the study. Again, the highest of three measurements was used for the analysis. Dyspnea was assessed subjectively as perceived shortness of breath, using the Borg scale: this is a visual analogue scale from 0 to 10, on which 0 represents absence of dyspnea and 10 is the maximum dyspnea. During the initial assessment and at each time point for reassessment, we evaluated wheezing and accessory muscle use. Wheezing was assessed through pulmonary auscultation and was ranked from 0 to 3 on an ascending scale of severity (0: no wheezing; 1: slight wheezing; 2: moderate wheezing; 3: severe wheezing). Accessory muscle use was also measured on a scale of increasing intensity (0: no accessory muscle activity: 1: slight activity; 2: moderate activity; 3: marked accessory muscle activity). When there was little wheezing or a silent chest plus marked accessory muscle use or signs of muscle fatigue, dyspnea was classified as severe. Individual and pooled analyses were performed for all parameters.

Criteria for improvement
Patients were evaluated for improvement at all assessment time points, to ensure patient safety and detect any possible need for additional interventions other than those provided for in the study protocol. For the purposes of this study, we considered the following definitions of improvement: 1) FEV1 and PEF ≥ 70% of those predicted for the age, sex, weight and height; and 2) improvement of dyspnea: a) Borg score < 2; 23 b) reduction of wheezing severity from baseline; and c) no accessory muscle use, as determined through observation of the sternocleidomastoid muscles.

Interim analysis
We planned to conduct an interim analysis at the time when the number of patients included had reached approximately half the predicted sample size, in order to decide whether to continue or to terminate inclusion. This analysis was carried out at the randomization and blinding center (Neuro-Sono Sleep Center) by a committee that was established specifically for this purpose.
After inclusion of 58 patients, this interim analysis committee suggested that recruitment for the study should be halted, since no difference between the treatments had been detected.

Adverse events
We actively evaluated the more frequent adverse events, such as dry mouth, tremor, palpitations, anxiety and headache, and recorded any other patient-reported events. 24,25 These variables were evaluated in terms of intention to treat (ITT).

Statistical analysis
The sample size was calculated considering a change in FEV1 of 0.37 liters, after treatment, as an indicator of improvement; a standard deviation of 0.85 liters; a significance level of 5%; and a statistical power of 80%. 16,22 This resulted in a sample size of n = 130 patients, i.e. 65 patients in each group. As noted above, interim analyses were carried out as planned after enrollment of 30 patients in each group; at that time, in view of the results, the interim analysis committee recommended termination of enrollment.
Quantitative variables were expressed as the mean ± SD, and categorical variables, as n (%). We used Student's t test for independent samples for normally distributed data, the Mann-Whitney U test for asymmetrically distributed data and Pearson's chi-square test or Fisher's exact test for categorical data. 26,27 Outcomes were assessed using ITT, considering the worst scenario, i.e. losses in the study group were considered treatment failures and losses in the control group, successful treatment. P-values < 0.05 were considered statistically significant.

Availability of data and materials
All the data generated and analyzed during this study are available upon contact with authors.

RESULTS
Thirty-one patients in the ciclesonide group and 27 patients in the hydrocortisone group were analyzed using ITT.

Demographic data
The ciclesonide and hydrocortisone groups ( Table 2) were similar with regard to age, systolic blood pressure (SBP), diastolic blood pressure (DBP) and the proportions of smoking, hypertension (HTN), diabetes mellitus (DM) and alcohol use. There were more women in the ciclesonide group (P < 0.001). The ciclesonide and hydrocortisone groups did not differ regarding vital signs and pulse oximetry ( Table 3). In within-group assessments, as expected, heart rate (HR) and respiratory rate (RR) were lower at hour 4, which was consistent with the clinical improvement observed in both groups. In between-group analyses, pulse oximetry and vital signs did not differ at hour 4.

Clinical variables
All the clinical parameters evaluated in this study showed improvement at hour 4, compared with entry to the emergency room. There was also no difference between the effects of ciclesonide and those of hydrocortisone at hour 4, i.e. both treatments were equally effective in improving respiratory effort, accessory muscle use, wheezing and Borg dyspnea scale scores ( Table 4).

Spirometric variables
The patients treated with inhaled ciclesonide and those treated with hydrocortisone exhibited similar forced vital capacity (FVC), FEV1 and PEF values and similar progression of these   parameters ( Table 5). At hour 4, neither the FVC nor the FEV1 values had changed from baseline in either group. PEF increased significantly from 30 minutes (baseline) to hour 4 (P < 0.001) in both groups, and both treatments were equally effective when compared head-to-head at hour 4 ( Table 6).

Adverse events
More patients in the hydrocortisone group complained of dry mouth, but there was no statistically significant difference in the frequency of any adverse effect between the groups (Table 7).

Hospitalization, losses and exclusions
Two patients in the ciclesonide group developed worsening bronchospasm and severe desaturation early in the course of treatment (having received only one dose of medication), and ultimately required ventilatory support.

DISCUSSION
To the best of our knowledge, this was the first double-blind randomized clinical trial to test high-dose inhaled ciclesonide for managing acute asthma in the emergency department. Our findings suggest that high-dose inhaled ciclesonide is as effective as intravenous hydrocortisone for this purpose. In this study, we tested ciclesonide as the intervention because it is a prodrug with high potency and less potential for oropharyngeal side effects than inhaled corticosteroid. This is particularly important for use in situations of acute exacerbations of asthma, a setting in which high doses of inhaled corticosteroids need to be administered. 12 Studies have shown that use of inhaled and systemic corticosteroids can decrease the length of emergency department stay and the hospitalization rate, when administered in the first hour of an acute asthma exacerbation. 16 Nevertheless, the optimal agent, dosage and duration of observation in the emergency department remain unknown. 20,28 Both drugs reduced expiratory effort, wheezing and accessory muscle use (Table 4); however, among the spirometric parameters analyzed, only PEF improved significantly from baseline at hour 4 in both groups ( Table 6). Adverse events, such as dry mouth, palpitations, tremor, headache and anxiety, did not differ between the two groups ( Table 7).   Table 7. Adverse events in the two groups CI = confidence interval. There was no significant difference between groups; dry mouth was the only complaint that was more prevalent in the hydrocortisone group.
Clinical studies using high doses of inhaled corticosteroids such as fluticasone, 16 flunisolide 17 and ciclesonide 11 also found these agents to be effective in increasing peak flow.
Although we did not enroll a large number of patients, the groups did not differ in terms of demographic characteristics, except for the higher proportion of women in the ciclesonide group ( Table 2). Two patients in the ciclesonide group, both with peak flow < 30% of the predicted flow, developed worsening bronchospasm and severe desaturation early in the course of treatment (having received only one dose of medication), and ultimately required invasive ventilation. Given the small sample, the likelihood of between-group differences was very high, and we judged these events to be attributable to chance.
Clinical parameters ( Table 4) and vital signs ( Table 3) were similar at admission to the emergency room and at hour 4. Only DBP was higher in the hydrocortisone group, possibly due to the systemic effects of the corticosteroid. 3 FVC and FEV1 remained unchanged from baseline to hour 4, and did not differ between the two groups. In previous studies on fluticasone 16 and flunisolide, 17 improvements in these parameters were reported. In our study, we observed an increase in PEF despite no increase in FEV1. This is consistent with the well-known mismatch between FEV1 and PEF in cases of acute severe asthma, [29][30][31] a condition in which FEV1 is underestimated and does not correlate adequately with rises in peak flow.
In a Cochrane review, it was noted that the higher cost of inhaled corticosteroids, compared with systemic corticosteroids, was an obstacle to use of the former. 28 However, this was not an issue in our study, in which nine puffs of ciclesonide (the total dose used in the emergency department) had an estimated cost of US$ 2.47, while a single 500-mg dose of hydrocortisone had a cost of US$ 3.18, thus making ciclesonide more cost-effective. In the United States, the average cost of treatment reaches US$ 1368.00, 30 days after a severe asthmatic exacerbation. 32 Also with regard to the cost and utility of inhaled corticosteroids, the FourFold Asthma Study (FAST) showed that it is clinically safe for patients to simply quadruple their usual dose of inhaled corticosteroids at home, upon deterioration of their condition, thus aborting a severe asthma attack and obviating the need for hospitalization. 33 The limitations of our study included the lack of follow-up (to assess for recurrence) and the small sample size. The latter had the consequence of, for instance, preventing us from determining whether dry mouth was truly more prevalent in the hydrocortisone group. The strengths of our study included its design and external validity, since we included adult patients from the general population with no restrictions regarding age, gender or ethnic group; rigorous evaluation of clinical and spirometric parameters; appropriate masking and blinding; and rigorous close monitoring of patients for a four-hour period during the study protocol.

CONCLUSION
In summary, our study suggests that high-dose inhaled ciclesonide is as effective as injectable hydrocortisone for managing acute severe asthma and had a similarly favorable adverse-event profile, with the advantage of being a prodrug that exerts topical anti-inflammatory effects while reducing the risk of long-term systemic side effects.