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Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay
ABSTRACT
Rationale: Several studies published in the second half of the 1990s have shown a therapeutic early effect of inhaled corticosteroids in acute asthma. However, systemic corticosteroids are considered the standard of care. Objectives: To compare the effect of repeated doses of inhaled fluticasone with the standard treatment of systemic corticosteroids in adult patients with severe acute asthma. Methods: One hundred six patients (mean age, 33.5 ± 8.8 years) were randomly assigned to receive fluticasone (3,000 e/hour) administered through a metered-dose inhaler and spacer at 10-minute intervals for 3 hours, or 500 mg of intravenous hydrocortisone. In addition, all patients received inhaled albuterol and ipratropium bromide. Main Results: Subjects treated with fluticasone showed 30.5 and 46.4% greater improvements in PEF and FEV1, respectively, compared with the hydrocortisone group. The fluticasone group had better PEF and FEV1 at 120, 150, and 180 minutes (p < 0.05). Also, the fluticasone group showed higher rates of patients who obtained the discharge threshold at 90, 120, and 150 minutes. This therapeutic benefit was particularly evident in those patients with the most severe obstruction. Subjects with a baseline FEV1 of less than 1 L treated with fluticasone showed a significant increase in pulmonary function (p = 0.001) and a significant decrease in hospitalization rate (p = 0.05). Conclusions: The use of repeated doses of inhaled fluticasone was more effective than intravenous hydrocortisone and was associated with an early improvement. This therapeutic benefit was particularly evident in those patients with the most severe obstruction.
Key Words: acute severe asthma albuterol corticosteroids emergency department treatment fluticasone
Systemic corticosteroids (SCS), together with frequent use of inhaled 2-agonists, anticholinergic drugs, and adequate oxygenation, are the basis of emergency department (ED) therapy for acute asthma (1, 2). The available evidence indicates that SCS require between 6 and 24 hours to produce therapeutic effects in terms of changes in pulmonary function or reduction of hospitalizations (3, 4). This time lag of hours agrees with the notion that the effects of SCS involve their binding to cytosolic glucocorticoid receptors, translocation of nuclear transcription factors, gene transcription, post-transcriptional mRNA regulation, and protein synthesis (the classic antiinflammatory or genomic model of steroid action) (5). On the contrary, inhaled corticosteroids (ICS) have been considered ineffective in acute asthma treatment. Nevertheless, several studies published in the second half of the 1990s have shown a therapeutic early effect (at 90eC120 minutes after administration) on pulmonary function; thus, high doses of fluticasone propionate (FP), flunisolide, or budesonide have been demonstrated to be superior to placebo in the treatment of adult (6, 7) and pediatric (8) patients with acute asthma. This acute therapeutic response suggests a different mechanism of action of topical character (nongenomic action) (9), related to a vasoconstriction at the level of the bronchial mucosa (10, 11). A recently published systematic review on the effectiveness of ICS in the ED treatment of acute asthma (12) concludes that there is a beneficial effect when they are compared with placebo. On the contrary, the four studies (all in children) in which ICS were compared against SCS showed contradictory results (13eC16). The objective of this clinical trial was to compare the effect of the use of high and repeated doses of inhaled FP with the standard treatment of SCS in adult patients with severe acute asthma.
METHODS
Patients
We recruited adult patients with acute asthma who were seen in the ED of the Hospital Central de las Fuerzas Armadas in Montevideo, Uruguay, over a 12-month period. This department sees approximately 65,000 patients annually, with approximately 1,300 visits/year for adult patients with acute asthma. The inclusion criteria for patients were as follows: (1) diagnosis criteria of asthma of the Global Strategy for Asthma Management and Prevention report (2); (2) age between 18 and 50 years; (3) a PEF rate or an FEV1 of less than 50% of predicted value; and (4) an expressed willingness to participate in the study, with written, informed consent obtained. Patients were excluded if they had a temperature higher than 38°C, or a history of cardiac, hepatic, renal, or other medical disease, or if they were pregnant. The hospital's ethics committees approved the study.
Design
Patients who fulfilled the inclusion criteria previously established were assigned in a double-blind, randomized manner to receive FP by means of a metered-dose inhaler into a spacer device (Volumatic; Allen and Hanburys Ltd., Greenford, UK; FP group) in a dose of two puffs at 10-minute intervals (3,000 e FP/hour), or intravenous hydrocortisone (HYD; 500 mg administered at the beginning of treatment; HYD group). In addition, all patients received four puffs of albuterol and ipratropium bromide (2,400 e of albuterol, and 504 e of ipratropium) each hour. Each puff was followed by two deep inhalations from the spacer, and the canister was shaken before each actuation. The protocol involved 3 hours of treatment. The hospital pharmacy prepared the treatments in random sequence using a random-number table in identical canisters and 5-ml syringes with barrels taped to prevent identification of contents, which were then numbered consecutively. For each study patient, the treatment nurse selected the next numbered canister and syringe from an opaque envelope, and all measures were made by physicians unaware of the patients' group assignment. The protocol included the administration of oxygen if SaO2 decreased to less than 92%.
Measures
The following variables were measured in each patient immediately before starting treatment and at 30-minute intervals for 3 hours after presentation: FEV1, PEF, respiratory rate, heart rate, accessory-muscle use, dyspnea, and wheezing. PEF was measured with a mini-Wright peak flow meter (Clement Clarke, Harlow, UK). The highest of three values was recorded. FEV1 was measured using a Vitalograph compact spirometer (Vitalograph Ltd., Buckingham, UK). Three successive maximal expiratory curves were recorded at each assessment, and the highest value was selected, according to the criteria of the American Thoracic Society (17). Heart rate was measured from continuous ECG. SaO2 was measured with a finger oximeter (Nellcor N-180 pulse oximeter; Nellcor, Hayward, CA). Accessory-muscle use was defined as visible retraction of the sternocleidomastoid muscles. Dyspnea was defined as the patient's own assessment of breathlessness. Wheezing was defined as musical or whistling breath sounds heard with a stethoscope during expiration. These clinical factors were graded in a scale from 0 to 3, in which 0 denoted absent, 1 mild, 2 moderate, and 3 severe. We defined a clinical index as the average of the three measures at 30-minute intervals (range, 0eC3). At the end of the therapy, the patient was asked to indicate the presence or absence of each of five symptoms: palpitations, tremor, anxiety, headache, and dry mouth. Also, an interviewer determined the duration of symptoms before presentation, which specifically included how long the patient had been wheezier and shorter of breath than usual; a decline in the PEF, if available, was considered. When it was possible, the patient's relatives were asked to confirm the patient's information. The decision to discharge or admit a patient was made at the end of protocol (180 minutes) by senior ED staff without knowledge of previous patient group allocation. Although some patients met discharge criteria during the study, none were discharged until the end of the protocol. Patients were discharged from the ED according to the following criteria: if accessory-muscle use was abated, if wheezing was judged minimal to completely resolved, if they were free of dyspnea, and if FEV1 or PEF was more than 60% of predicted. The physicians prescribed oral prednisone (60 mg for 7 days) for all discharged patients.
Primary outcome measures were improvement in pulmonary function (FEV1 or PEF) and admission rate. Secondary outcomes were clinical measures, respiratory and heart rates, SaO2, side effects, and proportion of patients that reached the discharge threshold during the 3 hours of treatment for each group.
Statistical Methods
All data were analyzed with an SPSS 10.0 for Windows software package (SPSS, Inc., Chicago, IL). Estimations from power calculations showed that the use of 104 subjects was sufficiently sensitive to detect a 0.37 L difference in FEV1, with = 0.05 and = 0.20 (i.e., with 80% power). In a previous study (18), we could estimate that the mean (± SD) final FEV1 value (expressed in liters) to be expected at 3 hours was 2.05 ± 0.85. Changes in FEV1 and PEF were evaluated using repeated-measures analysis of variance, with one between-subject factor (FP-HYD groups) and one within-subject factor (time). One-way repeated-measures analysis of variance was used to compare baseline values for each variable, after assessing both normality of distributions and homoscedasticity. When the F value indicated significant differences among group means, post hoc pairwise multiple comparisons were performed using the Scheffee test. To provide a graphical summary, Kaplan-Meier curves of the proportion of patients that reached the discharge threshold during the 3 hours of treatment were used. Baseline data of the two treatments were compared by t test for normally distributed independent samples, or the Mann-Whitney U test for nonnormally distributed continuous variables. Fisher's exact test was used for categoric variables. Multiple regression analysis was used to identify the best independent predictors of final pulmonary function. A p value of less than 0.05 using a two-tailed test was taken as significant for all statistical tests. Mean values ± SD and 95% confidence intervals (CI) were calculated for continuous variables. Clinical factors graded on a scale of 0 to 3 were reported as medians and interquartile ranges.
RESULTS
One hundred twenty-one patients were assessed in the ED. Of these, 15 (eight in the FP group and seven in the HYD group) patients were excluded because they did not meet the age requirement (nine patients) or PEF/FEV1 requirements (six patients). Of the remaining 106 patients (mean age ± SD, 33.5 ± 8.8 years), 52 were randomly assigned to the FP group and 54 to the HYD group. Analyses were by intention to treat, although no withdrawals occurred. The baseline characteristics of 106 patients are presented in Table 1. There were no significant differences between groups for the characteristics examined.
Figure 1 and Table 2 show PEF and FEV1 changes over time. Mean PEF improved significantly over baseline values for both groups (p < 0.001). The magnitude of PEF improvements over baseline values was significant at all times of treatment (p < 0.01). The two-way repeated measures analysis of variance showed a significant difference between groups (p = 0.03). The final improvements from baseline were 119.5 ± 66.3% for the FP group and 88.5 ± 62.9.1% for the HYD group. Subjects who received FP had an overall 30.5% (95% CI, 6.3eC54.7%; mean final difference, 52.7; 95% CI, 22.8eC82.5 L/minute) greater improvement in PEF than the HYD group. Compared with the HYD group, the FP group had better PEF at 120, 150, and 180 minutes (p < 0.05). The analysis of variance suggested that difference between groups increased with time (p = 0.001). The same pattern held for changes in FEV1. The improvement over baseline was significant in both groups (p < 0.01). There was a significant difference between both groups (p = 0.04). Subjects receiving FP had a 146.4 ± 92.3% L/minute improvement from baseline, and HYD subjects had a 100.2 ± 90.3% L/minute improvement from baseline. Patients who received FP had an overall 46.4% (95% CI, 11.2eC81.5%; mean final difference, 0.42; 95% CI, 0.17eC0.67 L) greater improvement in FEV1 from the HYD group. Also, difference between groups increased with time (p = 0.001).
At the end of protocol (3 hours), 11.1% (n = 6) of patients in the HYD group and 7.7% (n = 4) in the FP group were admitted (p = 0.7). However, Kaplan-Meier estimated curves of the proportion of patients that reached the discharge threshold during the 3 hours of treatment showed a significant difference in favor of the FP group (log-rank test, 0.0003; Figure 2) The FP group showed higher rates of patients who obtained the discharge threshold than the HYD group, at 90, 120, and 150 minutes. The proportions of patients (95% CI) at these treatment times were 65 (53eC76%), 85 (75eC95%), and 87% (77eC96%), respectively, in the FP group, and 35 (23eC46%), 37 (25eC48%), and 37% (25eC48%), respectively, in the HYD group. In the case of using a more demanding criterion of hospitalization (e.g., a cutoff for FEV1 > 70% of predicted), the admission rates would be 24.0% (n = 13) in the HYD group and 9.6% (n = 5) in the FP groups (p = 0.03).
In an attempt to predict pulmonary function at the end of treatment (FEV1 at 180 minutes), we performed a multiple regression analysis using three independent variables: treatment (HYD vs. FP), baseline FEV1, and duration of attack before ED visit. The analysis showed a model (R = 0.58, p = 0.001) with two variables (baseline FEV1 and treatment) as significant independent contributors of final pulmonary function. Previous duration of attack did not contribute significantly to the final pulmonary function. Consequently, subgroup analysis was performed dividing the patients according to the severity of obstruction at presentation (baseline FEV1 < 1 L vs. 1 L) and treatment (HYD vs. FP). Table 3 shows the main characteristics of subgroups. There was a tendency toward a predominance of males in those patients with baseline FEV1 of less than 1 L. Also, these patients showed a shorter duration of attack before ED; nevertheless, the difference did not reach statistical significance (p = 0.3). With the exception of pulmonary function and hospital admissions, there were no differences between subgroups in age, body mass index, smoking status, and previous use of -agonists and corticosteroids. FP subgroup patients with more severe obstruction showed a significant increase in pulmonary function (p = 0.001; Figure 3) and a decrease in hospitalization rate (3.8 in the FP group vs. 25% in the HYD group, p = 0.05) compared with the HYD group. Kaplan-Meier estimated curves of the proportion of patients that reached the discharge threshold during the 3 hours of treatment showed a significant difference in favor of the FP group (log-rank test, 0.004; Figure 4).
The repeated-measures analysis of variance showed a significant clinical index group effect (p = 0.04). FP patients presented a significantly lower score than the HYD patients at 90, 120, 150, and 180 minutes (p = 0.05). There was no difference between groups in heart rate (p = 0.5). The 3-hour mean heart rates were 114.7 ± 20.5 in the HYD group, and 110.1 ± 20.5 in the FP group (mean difference, 4.7; 95% CI, eC3.1 to 12.5). Despite use of continuous ECG recording, there were no signs of arrhythmia. Both groups produced nonsignificant increases in SaO2 (p = 0.4). The mean final SaO2 levels were 96.3 ± 2.0% in the HYD group and 96.8 ± 2.0% in the FP group (difference, eC0.6; 95% CI, eC1.3 to 0.2). Finally, there were nonsignificant differences between the HYD group and the FP group in the five side effects monitored: anxiety (42 and 38%), palpitations (22 and 17%), dry mouth (54 and 59%), tremor (40 and 37%), and headache (20 and 17%, respectively).
DISCUSSION
The objective of this randomized controlled study was to compare the effect of the use of high and repeated doses of inhaled FP with the standard treatment of intravenous HYD in adult patients with severe acute asthma. Data showed a significant advantage in the use of FP. This improvement was reflected in higher bronchodilator responses, lower clinical ratings, and minimal side effects. It is important to emphasize that this therapeutic effect was evident as soon as 90 minutes after ED presentation. Although the percentage of patients requiring hospitalization in the two groups was not significantly different, a more rapid improvement was seen in the FP group. Because SCS are believed to exert their effect over hours rather than minutes, one would expect a greater increase in the number of patients who obtain the discharge criteria with longer ED treatment times. Furthermore, the HYD group had a sudden increase in meeting the discharge criteria at 180 minutes compared with 150 minutes. This finding agrees with previous data from a systematic review on the effect of SCS in patients with acute asthma, which show a significant reduction of hospital admissions at 3 or 4 hours after the administration of SCS, but not before that time (4).
Because earlier studies indicated greater benefits of dual therapy, albuterol plus ipratropium bromide (18) or albuterol plus flunisolide (7), in patients with more severe airflow obstruction or with longer duration of attack before ED presentation, multivariate regression analyses were conducted to determine whether we could identify subgroups of patients that reacted differently to the treatment. Thus, like previous studies (7, 18, 19), baseline pulmonary function predicted final FEV1: patients most likely to benefit (greater improvement in pulmonary function) from the FP treatment were those with more severe baseline obstruction (FEV1 < 1 L). In addition, these patients had a significant reduction in the hospitalization rate. Although the patients with the most severe asthma had a trend toward a shorter duration of attack, the length of time of exacerbation did not predict final pulmonary function. This study agrees with others (7, 18, 19) that show that patients with acute asthma who present the greater therapeutic benefit are those with the most severe airway obstruction. This suggests that this subgroup of patients may be more sensitive to the drugs that improve bronchial obstruction, including ICS.
There are four randomized published studies comparing SCS (oral) with ICS for the treatment of acute asthma in the ED setting (all in children) (13eC16). Scarfone and coworkers (13) compared a single dose of nebulized dexamethasone (1.5 mg/kg) with oral prednisone (2 mg/kg) in 111 children aged 1 to 17 years. The study demonstrated no difference in the admission rate, but significantly more dexamethasone-treated children were ready for discharge from the ED at 2 hours. However, in contrast to FP, dexamethasone has a high bioavailability, and it is likely that it was active systemically. Volovitz and colleagues (14), in a small trial (22 children, 6eC16 years), reported no difference in pulmonary index score or PEF, with a single dose of budesonide (dry powder inhaler; 1.6 mg) or prednisone (2 mg/kg). However, the patients had mild episodes of acute asthma. Devidayal and colleagues (15) evaluated the efficacy of nebulized budesonide (800 e at half-hourly intervals for three doses) compared with a single dose of oral prednisolone (2 mg/kg) early in the ED treatment of 80 children (2eC12 years) with acute asthma. After 90 minutes of treatment, SaO2, respiratory rate, pulmonary index, and respiratory distress score were significantly improved in the budesonide group compared with the prednisolone group. In addition, the proportion of discharged patients at the end of treatment was significantly higher in the budesonide group than in the prednisolone group. Contrary to these studies, Schuh and coworkers (16) showed a significant advantage with a single dose of oral prednisone (2 mg/kg) compared with a single dose of 2 mg of FP, administered through a metered-dose inhaler with a spacer, in 100 children (5eC17 years) with severe exacerbation of asthma. In patients treated with FP, the hospital admission rate was significantly higher, and improvement in FEV1 at 4 hours was significantly lower than in prednisone-treated children.
Previous research found that SCS given in moderate or high doses reduce admissions and improve pulmonary function (3, 4); however, these effects are time-dependent (they require at least 3eC4 to 24 hours to occur). On the contrary, our findings showed that inhaled FP administered in high and sequential doses produces therapeutic effects as soon as 90 minutes after the beginning of treatment. It has been postulated (9) that effects of ICS in patients with acute asthma could result from a mechanism not related to genomic activity, in this manner causing substantial vasoconstriction in the larger airways and modifying some of the components of airway narrowing. In the last few years, it is becoming clear that corticosteroids have biological effects that are not mediated by the modulation of gene expression. Thus, several studies have shown that ICS cause acute vasoconstriction by potentiating noradrenergic neurotransmission in the airway vasculature. This nongenomic effect, which is transient and has a rapid onset, is plasma membraneeCassociated and does not involve the classic glucocorticoid receptors. These conclusions are based on a series of in vivo studies conducted in healthy subjects or in subjects with asthma (20eC23), and on in vivo studies using airway vascular smooth muscle obtained from donor lungs (24, 25). They have shown that FP produces a dose-dependent decrease in airway blood flow in healthy subjects and in subjects with asthma. The inhalation of 880 e of FP showed a nadir in airway blood flow between 30 and 60 minutes and a return to baseline by 90 minutes (20, 23). This effect was not specific for FP; it was also demonstrated for beclomethasone and budesonide (FP and budesonide have greater vasoconstrictor efficacy than beclomethasone) (23). The transient and dose-dependent nature of the vasoconstrictive properties of ICS was considered as scientific rationale for the dosing and delivery methodology used in this study. Therefore, inhaled FP was administered together with bronchodilators in the form of high and repeated or sequential doses as a way to obtain and maintain the effect throughout the time. The FP dose was calculated considering that previous studies showed that the inhalation of 3.0 mg/hour of flunisolide produced a significant increase of pulmonary function at 90 minutes (7, 19), and considering the higher topical potency of FP.
To our knowledge, this is the first randomized controlled trial evaluating the use of ICS compared with SCS in adult patients with severe acute asthma. In this study, a possible reason for the good outcome of the ICS group, just as in the study by Devidayal and coworkers (15), may have been that both protocols used high and repeated doses of ICS rather than a single dose, according to the transitory nature of the vasoconstriction effect. Thus, the single-dose protocols used in the remaining studies may have resulted in a suboptimal delivery of the drug into the lungs because of airway narrowing.
In conclusion, this study demonstrates that, in the ED treatment of adults with acute severe asthma, the use of repeated doses of inhaled FP were more effective than intravenous HYD and were associated with an early and more rapid improvement. This therapeutic benefit was evident particularly in those patients with the most severe obstruction. However, because there were no follow-up data on patients after discharge, this study is limited in terms of clinical outcome. These data suggest that, by causing vasoconstriction and possibly mucosal decongestion, ICS may have an immediate and nongenomic beneficial effect in acute asthma.
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