Abstract
Nebulized budesonide has been used successfully to treat acute asthma exacerbation, and we hypothesized that it could also be effective for exacerbations of chronic obstructive pulmonary disease (COPD). In this multicenter, double-blind, randomized, placebo-controlled trial, the efficacy of nebulized budesonide (Pulmicort Respules/Nebuamp), oral prednisolone, and placebo was compared in 199 patients with acute exacerbations of COPD requiring hospitalization. Patients received from randomization (H0) to 72 h (H72), 2 mg of budesonide every 6 h (n = 71), 30 mg of oral prednisolone every 12 h (n = 62), or placebo (n = 66). All received standard treatment, including nebulized β2-agonists, ipratropium bromide, oral antibiotics, and supplemental oxygen. The mean change (95% confidence interval) in postbronchodilator FEV1 from H0 to H72 was greater with active treatments than with placebo: budesonide versus placebo, 0.10 L (0.02 to 0.18 L); prednisolone versus placebo, 0.16 L (0.08 to 0.24 L). The difference in FEV1 between budesonide and prednisolone was not significant, − 0.06 L ( − 0.14 to 0.02 L). The occurrence of serious adverse events was similar for all groups. Budesonide had less systemic activity than prednisolone as indicated by a higher incidence of hyperglycemia observed with prednisolone. Both budesonide and prednisolone improved airflow in COPD patients with acute exacerbations when compared with placebo. Nebulized budesonide may be an alternative to oral prednisolone in the treatment of nonacidotic exacerbations of COPD but further studies should be done to evaluate its long-term impact on clinical outcomes after an initial episode of COPD exacerbation.
Keywords: chronic obstructive pulmonary disease; corticosteroid; exacerbation
Systemic corticosteroids are used to treat acute exacerbations of chronic obstructive pulmonary disease (COPD). This common clinical practice has been endorsed by medical societies (1, 2). Compared with placebo, systemic corticosteroids accelerate the recovery of flow rates and reduce the length of hospital stays of patients with nonacidotic, acute exacerbations of COPD receiving standard medical treatment with bronchodilators, antibiotics, and oxygen (3, 4). Despite proofs of efficacy, some concerns remain about using systemic corticosteroids to treat all patients with exacerbations of COPD. This is mainly because the short-term advantages of corticosteroids may be outweighed by the occurrence of adverse effects such as hyperglycemia, myopathy (5), and osteoporosis (6). Moreover, it has recently been reported that suppression of the adrenal response is common after short-term, high-dose corticosteroid treatment (7). In this context, the possibility of treating patients with acute exacerbations of COPD with inhaled corticosteroids having less systemic adverse effects is of particular interest.
Inhaled corticosteroids have a high level of topical anti-inflammatory activity and a low level of systemic activity (8, 9). Preliminary data have suggested that nebulized budesonide (BUD) might be an alternative to oral prednisolone (PRED) in the treatment of acute severe asthma (10). In 135 patients with acute severe asthma, no difference was found in the clinical efficacy of 20 mg nebulized BUD and either 30 or 160 mg oral PRED over 24 h (10). Nebulized BUD may also be sufficiently efficacious in the management of acute COPD exacerbation, but this has yet to be explored.
We hypothesized that BUD could be effective for the treatment of exacerbations of COPD. Accordingly, the objectives of the present study were to evaluate the efficacy and safety of BUD nebulized suspension (Pulmicort Respules/Nebuamp) compared with oral PRED and placebo in the treatment of patients with acute COPD exacerbations requiring hospitalization. The primary endpoints were the change in postbronchodilator (post-BD) FEV1 from baseline to 72 h, and the secondary endpoints included changes in blood gases, dyspnea score, and the occurrence of adverse events.
Patients with COPD who consulted the clinic or the emergency department for deterioration of their respiratory status and required hospitalization according to their attending physician were considered possible candidates for the study. The diagnosis of COPD was based on a clinical evaluation compatible with chronic bronchitis or emphysema as defined by the American Thoracic Society (ATS) (1). When available, baseline spirometry had to confirm the presence of irreversible airflow obstruction (post-BD FEV1 < 70% normal predicted value and FEV1/FVC < 70%). Patients were eligible if they had a recent (i.e., within ≤ 14 d) history of acute COPD exacerbation defined as increased breathlessness. Patients were included in the study if they were more than 50 yr old, had a smoking history of at least 20 pack-years, and according to the attending physician had to be treated in hospital. Patients were excluded if they had a personal history of asthma, allergic rhinitis, or atopy; were exposed to systemic corticosteroids in the preceding month; used more than 1,500 μg/d of inhaled beclomethasone equivalent; were at risk of imminent acute respiratory failure requiring mechanical ventilation or admission to the intensive care unit (pH < 7.30 and/or PaCO2 > 70 mm Hg, and/or PaO2 < 50 mm Hg despite supplemental oxygen); or if a specific cause for the exacerbation, such as pneumonia, pneumothorax, or heart failure, was diagnosed. The study was approved by the ethics committee at each participating institution according to local regulations, and written informed consent was obtained from all patients.
Thirty-four centers (Belgium, 3; Canada, 11; and France, 20) participated in this randomized, placebo-controlled, double-blind, double-dummy, parallel design study. The efficacy of the study medication was assessed from study entry (H0) to 72 h (H72). Patient safety was monitored during the treatment phase and the follow-up phase from Day 3 to Day 10. Patients were withdrawn from the study if confusion, lethargy, acute respiratory acidosis (pH < 7.30), or need for ventilatory assistance occurred. Patients could withdraw from the study at any time at their own discretion or at the discretion of the treating physician.
After consenting to participate in the study, eligible patients were randomly allocated to one of the three treatment groups, that is, BUD, PRED, or PLACEBO. The BUD group received BUD nebulized suspension (Pulmicort Respules/Nebuamp, 0.5 mg/ml, Astra Pharmaceutical Production, Sweden) 2 mg every 6 h for 72 h, and placebo tablets followed by inhaled BUD (Pulmicort Turbuhaler, 400 μg/puff, Astra Draco AB, Sweden) 2,000 μg/d (1,200 μg a.m. + 800 μg p.m.) with placebo tablets for 7 d. The PRED (Astra Draco AB, Sweden) group was treated with 30 mg by mouth every 12 h and placebo Pulmicort Respules/Nebuamp for 72 h followed by 40 mg/d oral PRED and placebo Turbuhaler for 7 d. The PLACEBO group received placebo nebulization and tablets for 72 h and placebo Turbuhaler and tablets for 7 d. To ensure the blindness of the study, opaque nebules were used for nebulized BUD and the matching placebo. Prednisolone tablets and placebo tablets were identical in appearance. Nebulized BUD and its matching placebo were delivered through a nontransparent Ventstream nebulizer and a PortaNeb-50 compressor (Medic-Aid Ltd., Bognor Regis, U.K.) in Belgium and France. Canadian patients received nebulized BUD through a nontransparent Ventstream nebulizer and Passport compressor (Invacare, Mississauga, Canada). The pressure and flow characteristics of the PortaNeb-50 and the Passport compressors were identical.
Immediately after each nebulization of BUD or PLACEBO, all patients received terbutaline nebulizer solution 5 mg (Bricanyl nebules; Astra Pharmaceutical Production, Sweden) or salbutamol solution 2.5 mg and ipratropium bromide 0.5 mg (Atrovent solution; Boehringer Ingelheim, Ingelheim, Germany). Patients could also be given nebulized terbutaline or salbutamol as rescue medication. Methylxanthines were allowed if prescribed before the study as a regular therapy. It was recommended that all patients receive mono- or combined, oral antibiotic therapy with the following: amoxicillin/clavulinic acid (Augmentin or Clavulin; SmithKline Beecham, UK), ciprofloxacin (Ciprox or Cipro; Bayer Pharma, Leverkusen, Germany), cefuroxime axetil (Zinnat or Ceftin; Glaxo Wellcome, Meadoway, UK). Antibiotics were used in 83%, 84%, and 80% of patients in the BUD, PRED, and PLACEBO groups, respectively. Supplemental oxygen therapy was used as needed to maintain SaO2 > 90%.
Patients were assessed every 12 h during the acute phase (from H0 to H72), at hospital discharge, and at Day 10. Spirometry was carried out before and 15 to 30 min after bronchodilator (BD) nebulization (β2-agonist and ipratropium bromide) according to ATS standards (11). Dyspnea was assessed according to the modified Borg scale (12). Arterial blood samples were taken at study entry, 24, 48, and 72 h for the determination of PaO2 , PaCO2 , and pH, regardless of whether the patient was on room air or on supplementary oxygen. Safety of the study medication was assessed by monitoring the occurrence of any adverse event during the acute and follow-up phases of the study. Complete blood cell counts, including eosinophils, were obtained at entry, and blood glucose, sodium, potassium, and chloride were measured at H0 and H72.
The primary variable to assess treatment efficacy was the change in post-BD FEV1 from H0 to H72. Secondary endpoints included the changes in pre-BD FEV1, dyspnea score, and arterial blood gases from H0 to H72, duration of hospitalization, and occurrence of adverse events. An adverse event was defined as any medical event reported by the patients from study entry to Day 10. Serious adverse events included death, life-threatening events, and events resulting in prolongation of hospitalization or readmission to hospital. Study discontinuation due to adverse events, including COPD deterioration or relapse, was also monitored. Deterioration of COPD while patients were hospitalized was defined as the need for treatment intensification according to the treating physician, the development of confusion, lethargy, acute respiratory acidosis (PaCO2 ⩾ 70 mm Hg with a pH < 7.30 or an increase in PaCO2 ⩾ 10 mm Hg), or need for ventilatory assistance. After discharge, deterioration of COPD was defined as an unscheduled visit triggered by any exacerbation of respiratory symptoms requiring additional respiratory medications. Clinical improvement was assessed according to the following indicators of success: an increase in FEV1 of at least 0.15 L and a reduction in PaCO2 of at least 5 mm Hg. Clinical deterioration of patients' COPD from H0 to H72 was assessed according to the judgment of the treating physician.
Efficacy analysis was based on the intention-to-treat principle and the last value carried forward method was applied where data were missing. Changes in FEV1 and blood gases from baseline were analyzed by means of an analysis of covariance with baseline values as covariate. Means and 95% confidence intervals (95% CI) of the differences between treatment groups were estimated by least square methods. A chi-square analysis of the clinical indicators of success was used to compare the number of patients in each group. Hospitalization time was analyzed by means of a log-rank test; patients who discontinued the study and who were not discharged before discontinuing were classified as not discharged at the end of the study. We calculated that 63 patients in each group would give 80% power to detect a 0.15 L difference in FEV1 between two treatment means at a 0.05 significance level with a standard deviation (SD) of 0.30 L.
It was possible to ensure a formal screening procedure in all the participating centers for the first 11 mo of this 20-mo study. During this period, 687 patients were screened, from which 75 (11%) were enrolled. The main reasons for exclusion were the use of systemic corticosteroids in the preceding month (36%), not fulfilling the criteria for the diagnosis of COPD or acute exacerbation (28%), and unwillingness to participate in the study (22%).
A total of 199 patients were finally randomized (Figure 1). Seventy-one patients were randomly assigned to nebulized BUD, 62 to PRED, and 66 to PLACEBO (Figure 1). Twenty-eight patients were withdrawn from the study during the acute phase for the following reasons: adverse events (n = 12), treatment failure according to the evaluation of the attending physician (n = 9), inclusion or exclusion criteria not fulfilled (n = 4), need for a prohibited medication (n = 2), and withdrawal of patient's consent (n = 1). The proportion of drop-outs during the acute phase was similar in the three groups: 10 patients (14%) in the BUD group, 7 (11%) in the PRED group, and 11 in the PLACEBO group (17%). Another 24 patients discontinued the study during the follow-up phase. At Day 10, 51 patients (72%) in the BUD group, 52 patients (84%) in the PRED group, and 44 patients (67%) in the PLACEBO group were assessed.
Patient characteristics at study entry are presented in Table 1. Age, smoking history, FEV1, blood gases, serum glucose, eosinophil count, and the use of concomitant drugs were similar between the three groups. Spirometry results were obtained on 137 (69%) patients in the stable state but stable state data could not be obtained on the remaining 62 patients.
| Group | BUD (n = 71) | PRED (n = 62) | PLACEBO (n = 66) | |||
|---|---|---|---|---|---|---|
| Sex, M/F | 57/14 | 52/10 | 53/13 | |||
| Age, yr | 69.1 (8.7) | 70.4 (7.7) | 70.4 (8.9) | |||
| Current smoker, n (%) | 31 (44%) | 22 (35%) | 23 (35%) | |||
| No. of pack-years | 55.5 (30.0) | 56.6 (30.5) | 55.9 (23.2) | |||
| Time since onset of exacerbation, d | 6.5 (4.1) | 5.7 (3.7) | 6.8 (5.1) | |||
| Post-BD FEV1 at stable state, L† | 1.14 (0.45) | 1.17 (0.49) | 1.13 (0.44) | |||
| FEV1 at H0, L | ||||||
| Pre-BD | 0.83 (0.34) | 0.86 (0.36) | 0.75 (0.35) | |||
| Post-BD | 0.94 (0.41) | 0.96 (0.44) | 0.86 (0.41) | |||
| PaO2 , mm Hg | 65 (12) | 65 (13) | 63 (15) | |||
| PaCO2 , mm Hg | 44 (8) | 43 (7) | 44 (8) | |||
| pH | 7.41 (0.03) | 7.42 (0.03) | 7.41 (0.04) | |||
| Eosinophils, 106/L | 188 (188) | 174 (198) | 175 (188) | |||
| Glucose, mmol/L | 6.05 (3.24) | 6.10 (2.34) | 6.49 (1.99) | |||
| Concomitant treatment‡ | ||||||
| Inhaled corticosteroids, n (%) | 36 (51%) | 37 (60%) | 38 (58%) | |||
| β2-agonists, n (%) | 66 (93%) | 60 (97%) | 56 (85%) | |||
| Ipratropium bromide, n (%) | 55 (77%) | 48 (77%) | 44 (67%) | |||
| Xanthines, n (%) | 23 (32%) | 17 (27%) | 23 (35%) | |||
| Antibiotics, n (%) | 30 (42%) | 25 (40%) | 26 (39%) |
The means (and 95% CIs) for the changes in post-BD FEV1 from H0 to H72 of the three groups are shown in Figure 2. There was a greater improvement in FEV1 from H0 to H72 in both treatment groups compared with placebo: BUD versus PLACEBO, 0.10 L (0.02 to 0.18 L); PRED versus PLACEBO, 0.16 L (0.09 to 0.24 L). Although the improvement in FEV1 tended to be smaller in the BUD group compared with the PRED group, this difference was not statistically significant, BUD-PRED −0.06 L (−0.14 to 0.02 L). The time-course of post-BD FEV1 for the three treatment groups is shown in Figure 3. The use of nebulized BUD and PRED was associated with a faster rate of improvement in FEV1 compared with PLACEBO. For patients for whom a steady-state FEV1 was available, the rate of FEV1 recovery could be calculated. At H0, the means of the post-BD FEV1 values were 80%, 82%, and 81% of the stable state values in the BUD, PRED, and PLACEBO groups, respectively. At H72, the corresponding values were 94%, 94%, and 85% in the BUD, PRED, and PLACEBO groups, respectively.
Fig. 2. Mean and 95% CI for the difference in change in post-BD FEV1 from H0 to H72 among the three treatment groups.
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Fig. 3. Time-course of post-BD FEV1 for the three treatment groups from H0 to H72. ▴ Prednisone; ▪ budesonide; • placebo.
[More] [Minimize]Valid measurements of pre-BD FEV1 were difficult to obtain, especially at study entry, because of the frequent use of rescue bronchodilator. Pre-BD FEV1 improved in both active treatment groups from H0 to H72. However, the change in pre-BD FEV1 during this period was statistically significant compared with PLACEBO only in the PRED group: BUD versus PLACEBO, 0.05 L (−0.03 to 0.13 L); PRED versus PLACEBO, 0.12 L (0.03 to 0.21 L).
The reduction in Borg scale ratings was of comparable magnitude in the three groups (mean Borg scale unit ± SD): BUD, 1.9 ± 2.3; PRED, 2.6 ± 2.3; and PLACEBO, 1.8 ± 2.6. The improvement in arterial PaO2 from H0 to H72 was significant compared with PLACEBO (4 mm Hg ± 12) in the PRED group (7 mm Hg ± 14 p < 0.05) but not in the BUD group (3 mm Hg ± 11). In contrast, the decline in PaCO2 was significantly greater in the two active treatment groups than in the PLACEBO group (−1 mm Hg ± 4, −1 mm Hg ± 5, and 1 mm Hg ± 6, in the BUD, PRED, and PLACEBO groups, respectively; p < 0.05, between active treatments and placebo). The consumption of rescue medication was low and similar in the three groups.
The proportion of patients showing clinical indicators of success or failure in the three treatment groups is provided in Table 2. The proportion of patients showing at least 0.15 L improvement in FEV1 was greater in the BUD and PRED groups compared with PLACEBO (p < 0.05). In the PRED group, a larger proportion of patients showed a reduction in PaCO2 ⩾ 5 mm Hg compared with placebo and BUD (p < 0.05). The occurrence of COPD deterioration from H0 to H72 was comparable among the three treatment groups.
| BUD (n = 71) | PRED (n = 62) | PLACEBO (n = 66) | ||||
|---|---|---|---|---|---|---|
| ↑ post-BD FEV1 ⩾ 0.15 L from H0 to H72 | 24 (34%)a | 30 (48%)a | 12 (18%)b | |||
| ↓ PaCO2 ⩾ 5 mm Hg | 9 (13%)c | 17 (27%)d | 6 (9%)c | |||
| Clinical deterioration of COPD† | 2 (3%) | 3 (5%) | 3 (5%) |
Eosinophil counts at H72 were available for 108 patients (mean × 106 cells/L ± SD): BUD (n = 40), 184 ± 158; PRED (n = 30), 31 ± 73; and PLACEBO (n = 38), 356 ± 291. Blood sodium, potassium, and chloride were similar between groups at baseline and at H72. Blood glucose was slightly increased in the PRED group at H72.
Forty-two percent, 35%, and 48% of patients were still hospitalized at Day 10 in the BUD, PRED, and PLACEBO groups, respectively (p = not significant [NS], between active treatments and placebo). There was no statistical difference regarding the median duration of hospitalization; 7, 6, and 8 d in the BUD, PRED, and PLACEBO groups, respectively.
The overall occurrence of adverse events over the study period was similar for the three groups (Table 3). One patient in the PRED group who had a history of coronary artery disease and cardiothyrotoxicosis died suddenly at home during the follow-up period. The exact cause of death has not been established. The most common serious adverse event was COPD deterioration leading to a prolongation of hospitalization or rehospitalization in three, two, and four patients in the BUD, PRED, and PLACEBO groups, respectively. One patient in the PLACEBO group required intubation and mechanical ventilation for 3 d. The most common cause of study discontinuation was COPD deterioration or relapse. A greater proportion of patients developed hyperglycemia in the PRED group (n = 7) compared with BUD (n = 1) and PLACEBO (n = 0). Two of the seven episodes of hyperglycemia occurring in the PRED group required insulin therapy.
| BUD (n = 71) | PRED (n = 62) | PLACEBO (n = 66) | ||||
|---|---|---|---|---|---|---|
| Adverse event(s)† | ||||||
| Any | 38 (53) | 43 (69) | 40 (61) | |||
| Hyperglycemia | 1 (2) | 7 (10) | 0 (0) | |||
| Serious adverse event(s)‡ | ||||||
| Any | 8 (11) | 5 (8) | 9 (14) | |||
| Leading to prolonged hospitalization or rehospitalization | 3 (4) | 2 (3) | 4 (6) | |||
| Study discontinuation§ | ||||||
| Due to any adverse events | 12 (17) | 6 (10) | 12 (18) | |||
| Due to COPD deterioration | 5 (7) | 3 (5) | 8 (12) |
In this study, we evaluated the short-term efficacy and safety of nebulized BUD compared with placebo and systemic corticosteroids for the treatment of acute exacerbation of COPD. As in other studies, we found that systemic corticosteroids successfully improved airflow rates in patients with acute exacerbation of COPD requiring hospitalization (3, 4, 13). Our study, however, is the first to demonstrate the efficacy of inhaled corticosteroids in the treatment of patients with acute, nonacidotic exacerbations of COPD. The efficacy of nebulized BUD and PRED for the improvement of airflow rates and for the prevention of serious adverse events and deterioration of COPD in the 10-d period after study entry was comparable. Compared with PRED, nebulized BUD was associated with a lesser occurrence of hyperglycemia, a potential advantage for patients with COPD having such comorbid condition.
In the PRED group, the proportion of patients showing a substantial decrease in PaCO2 (i.e., ⩾ 5 mm Hg) was significantly larger than in the BUD or placebo groups, and there was a tendency for more patients to show a large increase in post-BD FEV1 (i.e., ⩾ 0.15 L) compared with the BUD group. This suggests that systemic corticosteroids may be more effective than nebulized BUD as used in the present study in some patients. This may be particularly important in patients with imminent acute respiratory failure requiring ventilatory support or admission to an intensive care unit. It is possible that a higher dosage of BUD or more frequent inhaled corticosteroid administration, as reported for the treatment of asthma exacerbations, might have provided greater efficacy in the inhaled corticosteroids treated group (10, 14).
Our study and others have established that systemic corticosteroids effectively improve the short-term clinical outcome of patients with acute exacerbations of COPD (3, 4, 15). Compared with placebo, systemic corticosteroids accelerate the recovery of FEV1 and reduce the length of hospital stays by approximately 1 d (3, 4). However, after the initial improvement, the advantages of systemic corticosteroids over placebo become less obvious. At 2 wk, the difference in improvement in FEV1 between placebo and corticosteroids is no longer significant (3, 4). Systemic corticosteroids may reduce the need for additional therapy for COPD for up to 90 d after the exacerbation, but the rate of serious adverse outcomes, such as intubation, hospital readmission, and death, has not been shown to decrease compared with placebo (3, 4). The evaluation of the long-term impact of nebulized budesonide on clinical outcomes such as relapse or worsening of COPD after an initial episode of COPD exacerbation was beyond the scope of the present study and should be the topic of future work.
Another important aspect to consider in the evaluation of the risk/benefit ratio of using systemic corticosteroids in the treatment of exacerbations of COPD is that patients with advanced COPD often are elderly people with comorbid conditions. Typically, they have multiple exacerbations during the course of their disease and are likely to be exposed to repeated short courses of systemic corticosteroids (16). The adverse effects of corticosteroid drugs are related to the cumulative dose to which a given individual has been exposed. Although the intermittent use of systemic corticosteroids is not as deleterious as continuous use, the risk of osteoporosis (6) and myopathy (5) may still be significantly increased in patients treated with repeated short courses. These serious corticosteroid-related complications are associated with significant impacts on quality of life and health care–related costs (17). Therefore, the long-term risk/benefit ratio of systemic corticosteroids in the treatment of acute exacerbation of COPD is probably not favorable. Inhaled corticosteroids may be a useful option for the treatment of exacerbations of COPD and help to reduce the cumulative exposure of patients to systemic corticosteroids.
The magnitude of improvement in post-BD FEV1 in the PRED group was comparable to that found in a similar patient population (3). Therefore, the comparable improvement in FEV1 found in both groups treated with corticosteroids is unlikely to be explained by a smaller effect of prednisolone on FEV1 in our study. As in other studies evaluating the role of corticosteroids in the treatment of acute exacerbations of COPD, only a minority of screened patients were eligible for entry into the study (3, 4). The most frequent reason for excluding patients was exposure to systemic corticosteroids in the preceding month. As more patients are treated with corticosteroids earlier in the course of exacerbations, it is not an uncommon clinical situation to evaluate patients with acute exacerbations who are already receiving systemic corticosteroids. It is possible that the response to corticosteroids differs in these patients compared with those who have not been exposed recently to systemic corticosteroids.
Compared with previous studies (3, 4), the length of hospitalization was not significantly reduced by the use of corticosteroids in our study. Importantly, this is unlikely to be explained on the basis of a suboptimal dose of corticosteroids, since a 2-d reduction in hospital stay was previously demonstrated in patients treated with 30 mg prednisolone daily compared with those receiving placebo (4). The present investigation was an international and multicenter study and the actual length of hospital stay was recorded. The variability of this parameter may have been greater than in previous studies (3, 4) owing to differences in medical practice, including organization of health care, therefore decreasing the probability of detecting a significant reduction in hospitalization duration.
In summary, both nebulized BUD and oral PRED improved airflow obstruction in patients with acute exacerbations of COPD. Budesonide had less systemic activity than prednisolone as indicated by a higher incidence of hyperglycemia with prednisolone. Our study suggests that nebulized BUD may be an alternative to oral PRED for the treatment of patients with acute, nonacidotic exacerbations of COPD. Future studies should be done to evaluate the long-term impact of nebulized budesonide on clinical outcomes such as relapse or COPD deterioration after an initial episode of COPD exacerbation.
The authors wish to thank the following investigators: Canada: Dr. Abboud, Dr. Beveridge, Dr. Borkent, Dr. Cosio, Dr. FitzGerald, Dr. Fletcher, Dr. Grunfeld, Dr. LeBlanc, Dr. Lecours, Dr. McIvor, Dr. Olivenstein, Dr. Renzi, Dr. Shragge, C. Barber, M. Bélanger, M. J. Breton, J. Buchanan, K. Fugeres, G. Gerardi, G. Lebeuf, S. Milencoff, S. Murphy, C. Nogue, R. Pelletier, L. Pruszewski, C. Rossignol, J. Rousseau, J. Roy, R. Simard; France: Dr. Perez, Dr. Salez, Pr. Didier, Dr. Elloumi, Dr. Lacassagne, Dr. Lemerre, Dr. Proust, Dr. Gazevic, Dr. Herer, Dr. Roig-Morisseau, Dr. Zuck, Dr. Arnulf, Dr. Attali, Pr. Diot, Dr. Rivoire, Dr. Kessler, Pr. Weitzenblum, Dr. Badatcheff, Dr. Boulet, Pr. Racineux, Pr. Muir, Dr. Teugang, Dr. Bard, Dr. Salmeron, Dr. Pointet, Pr. Pariente, Dr. Reffas, Dr. Roue, Dr. Durieu, Dr. Chavaillon, Dr. Lerousseau, Dr. Leroyer, Dr. Quiot, Pr. Godard, Dr. Oliver, Pr. Polu, Dr. Ficheroulle, Dr. Delhoume, Dr. Noumri, Dr. Staali, Dr. Boyer, Dr. Castelnau; Belgium: Dr. Aumann, Dr. Lambrechts, Dr. Dockx, Dr. Van Den Brande, Dr. Valck, Dr. Van Duffel, Mme Van Houtte, Dr. Mercenier, Mme Teucq, Mr. Duwez, Dr. Vandermoten, Dr. Cerny, Dr. Vanpee.
Supported by Laboratories Astra France, Astra Canada, and Astra Belgium.
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The authors would also like to acknowledge the support of AstraZeneca Canada, Dr. Robert Jenkins, and Ms. Joanna Lee for assistance in reviewing and preparing the manuscript, and AstraZeneca R&D Lund, Kurt Nikander for his advice.
