ORIGINAL RESEARCH ARTICLE

Clin Drug Invest 2003; 23 (1): 55-62 1173-2563/03/0001-0055/$230.00/0 Adis International Limited. All rights reserved.

Comparison of the Efficacy of Nebulised Budesonide with Parenteral Corticosteroids in the Treatment of Acute Exacerbations of Chronic Obstructive Pulmonary Disease
A. Mirici, M. Meral and M. Akgun
Chest Diseases Department, Faculty of Medicine, Atatrk University, Erzurum, Turkey

Abstract

Objective: To compare the efficacy and safety of nebulised budesonide and systemic corticosteroid in the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD). Design: Randomised, double-blind, placebo-controlled, parallel-group trial. Patients and interventions: A total of 40 patients who had moderate to severe acute exacerbations of COPD and required hospitalisation were enrolled in the study. The patients were randomised to receive either nebulised budesonide 8mg daily (n = 21) or systemic (intravenous) prednisolone 40mg daily (n = 19). Airway obstruction (peak expiratory flow rate [PEFR]) and gas exchange (arterial partial pressure of oxygen [PaO2] and carbon dioxide [PaCO2], pH and oxygen saturation [SaO2]) were evaluated at 30 min, at 6, 24 and 48 hours, and at day 10. Results: There were no significant differences between groups at baseline. In both groups, differences were significant for PEFR, SaO2 and PaO2 (p < 0.001), but not for PaCO2 and pH, in comparison with their baseline values. There were no significant differences between groups for all parameters (PEFR, PaO2, PaCO2, pH and SaO2) at all time periods. No adverse events were recorded in either group. Conclusions: Our study suggests that nebulised budesonide may be an alternative to parenteral corticosteroids in the treatment of acute exacerbations of COPD.

Chronic obstructive pulmonary disease (COPD) has a chronic and progressive course; however, admission of patients with COPD increases during acute exacerbations. Patients with COPD may experience acute exacerbations one to four times in a year. Periods of acute exacerbations are important

because of increased morbidity and mortality and healthcare costs.[1] There are still unclear areas in the standard management of acute exacerbations of COPD, for instance on the use of corticosteroids. Corticosteroid use is recommended as an addition to bron-

56

Mirici et al.

chodilator, oxygen and antibacterial treatment for moderate to severe acute exacerbations of COPD in patients treated on an inpatient basis.[2,3] However, there are few studies on corticosteroid use in nebulised form. The role of inflammation in the pathogenesis of COPD has been emphasised, and it has been demonstrated that in acute exacerbations of COPD there are changes in the characteristics of inflammation and increases in eosinophils similar to those in asthma.[2-5] It has been known for a long time that corticosteroids are effective in asthma in both the stable and acute exacerbation phases.[6,7] In stable COPD, use of inhaled or systemic corticosteroids does not provide as dramatic benefits as in asthma.[8,9] There are a lot of studies about the usefulness of systemic corticosteroids in acute exacerbations of COPD,[10] but the dose and duration of the treatment are still uncertain.[11] The results of studies with high-dose nebulised corticosteroids in acute exacerbations of asthma are similar to those with systemic corticosteroids.[12,13] Use of nebulised corticosteroids in the treatment of acute exacerbations of COPD seems reasonable, because both diseases have inflammatory characteristics in the acute exacerbation periods. Additionally, the possible adverse effects of systemic corticosteroid treatment may be more problematic in elderly patients with COPD than in those with asthma. This study was conducted to compare the efficacy and safety of nebulised budesonide with systemic corticosteroid in the treatment of acute exacerbations of COPD . Patients and Methods
Patients

were classified as having had a mild, moderate or severe attack according to their clinical status.[1] Patients were included in the study if they had moderate to severe acute attacks of COPD. Exclusion criteria were exposure to systemic corticosteroids in the preceding month; presence of asthma, allergic rhinitis, atopy or any systemic disease (such as diabetes mellitus or hypertension); and being at risk of acute respiratory failure requiring mechanical ventilation. The study protocol was approved by the local ethics committee at the Research Hospital of the Faculty of Medicine. Patients provided written informed consent after baseline evaluation.
Study Design

The study was designed as a randomised, double-blind, parallel trial. The efficacy of the study medications was assessed from the beginning of the study to the tenth day. Follow-up times were 30 minutes, 6, 24 and 48 hours, and 10 days. The safety of the patients was monitored during treatment by investigators and consultant specialists. Patients were withdrawn from the study if acute respiratory acidosis or a need for mechanical ventilation occurred; these patients received appropriate treatment. Randomisation was performed using unmarked, ordered, sealed envelopes. No stratification method was used for randomisation. The randomisation order was determined using a computer-generated list of random numbers.
Treatment

Patients with COPD admitted to the emergency department of our hospital for increased symptoms and requiring hospitalisation were included in the study. For all patients, the diagnosis of COPD was established as defined by the American Thoracic Society (ATS), and all of them had previously been followed up at the outpatient clinic. Thus none of them had postbronchodilator reversibility. Patients
Adis International Limited. All rights reserved.

Eligible patients who had moderate or severe acute attacks were randomly allocated to one of the two treatment groups: parenteral corticosteroid (PS) or nebulised corticosteroid (NS). Treatment in the PS group consisted of prednisolone 40mg (intravenous ampoule) and a placebo nebulised suspension (placebo Respules1); treatment in the NS group consisted of nebulised budesonide sus1 Use of tradenames is for product identification only and does not imply endorsement.
Clin Drug Invest 2003; 23 (1)

Nebulised Corticosteroids in COPD

57

pension (Pulmicort Respules/Nebuampul 0.5 mg/ml; Astra-Zeneca Pharmaceutical Production) and an intravenous placebo (intravenous saline) for 10 days. Budesonide and placebo Respules were given as 4mg twice daily; prednisolone and placebo were given once daily intravenously. All medications and placebo were identical. Nebulisation procedures were performed by jet nebuliser (Porta Neb Ventstream 1803; MedicAid) with 80% of output of less than 5m. Patients received standard treatment with a nebulised agonist (salbutamol 3.01mg) and anticholinergic (ipratropium bromide 0.5mg) combination every 6 hours, intravenous aminophylline (0.5 mg/kg/h) and oral or intravenous antibacterials at the discretion of the admitting physician. Supplementary oxygen therapy was used to maintain oxygen saturation (SaO2) >90%.
Measurements and Assessments

Statistical Analysis

Pearsons chi-square test and the Mann-Whitney test were used to compare baseline values between groups. For comparison of changes in parameters between and in groups, the repeated measures analysis of variance test was used. For evaluation of variations in each step of assessment in relation to baseline values, the Mann-Whitney test was used. The data were analysed using SPSS version 9.0 (SPSS Inc.). The mean values of all steps and 95% CIs in each group were calculated. A p-value of <0.05 was considered significant. Results A total of 44 patients were randomised, from which 22 were randomly assigned to the PS group and 22 to the NS group. Four patients were withdrawn from the study for the following reasons: required mechanical ventilation (n = 1, PS group), pneumothorax (n = 1, NS group) and asked to be discharged from hospital (n = 2, NS group). Twenty-one of 40 patients who completed the study were administered parenteral treatment and 19 of them were administered nebulised treatment. Demographic characteristics and baseline values of the groups are summarised in table I. Baseline values of the groups were not significantly different (p > 0.05). In each group, it was found that increases in PEFR, PaO2 and SaO2 values within the groups were statistically significant (p < 0.001 for all parameters). Changes in pH and PaCO2 values in each
Table I. Comparison of baseline characteristics of the two groups Characteristic Age (y) Sex (F/M) Baseline PEFR (%) Baseline PaO2 (mm Hg) Baseline PaCO2 (mm Hg) Baseline SaO2 (%) Baseline pH PS group 64.80 5/16 32.85 42.68 45.23 75.37 7.359 NS group 63.06 6/13 34.32 44.65 40.08 79.74 7.410 p-Value 0.73 0.42 0.63 0.60 0.14 0.45 0.14

All patients were hospitalised after baseline evaluations, which consisted of measurements of peak expiratory flow rate (PEFR) and/or forced expiratory volume in 1 second (FEV1) and arterial blood gas analysis. PEFR measurements were carried out by Wright PEF meter. All patients exhaled three times and the highest value was recorded as the baseline value. Spirometry was carried out by computerised spirometer (Sensor Medics, Vmax22). However, this procedure could not be applied to all patients due to the physical restrictions of our clinic (the procedure is not available in our inpatient clinic, and there is a considerable distance between the in- and outpatient clinics). PEFR measurements were done according to a similar design at all time periods. Arterial blood samples were taken at baseline and during the study at 30 minutes, 6, 24 and 48 hours and day 10 for measurement of arterial partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2), SaO2 and pH. Patients were on room air at baseline and on day 10, but on supplementary oxygen at 30 minutes and 6, 24 and 48 hours.
Adis International Limited. All rights reserved.

NS = nebulised corticosteroid group; PaCO2 = arterial partial pressure of carbon dioxide; PaO2 = arterial partial pressure of oxygen; PEFR = peak expiratory flow rate; PS = parenteral corticosteroid group; SaO2 = arterial oxygen saturation.

Clin Drug Invest 2003; 23 (1)

58

Mirici et al.

Table II. Mean values in the groups at different follow-up times Parameter PEFR (%) PS NS PaO2 (mm Hg) PS NS PaCO2 (mm Hg) PS NS SaO2 (mm Hg) PS NS pH PS NS 7.350 7.410 7.396 7.408 7.394 7.420 7.378 7.415 7.393 7.404 7.392 7.411 75.30 79.70 85.75 87.71 87.10 87.03 88.01 88.50 90.41 89.26 93.09 92.64 45.20 40.00 42.05 39.86 43.15 38.82 43.54 40.01 41.78 40.59 41.70 39.68 42.60 44.60 55.06 59.81 55.80 55.34 58.18 57.31 64.75 60.55 68.89 63.65 32.80 34.30 37.50 36.00 39.50 39.81 42.20 42.87 45.90 48.94 50.65 56.69 Baseline 30 min 6h 24h 48h Day 10

NS = nebulised corticosteroid group; PaCO2 = arterial partial pressure of carbon dioxide; PaO2 = arterial partial pressure of oxygen; PEFR = peak expiratory flow rate; PS = parenteral corticosteroid group; SaO2 = arterial oxygen saturation.

PaO2 (mm Hg)

group were not statistically significant (p > 0.05). Average values for all parameters during the study are summarised in table II. In a comparison between the groups, it was found that there were no significant differences between percentage changes in PEFR, PaO2 and
100

100

NS group

PS group

80

60

NS group

PS group

80

40

PEFR (%)

60

20
se lin 30 e m in 6h se lin 30 e m in 6h h 48 h ay 10 D Ba Ba D h 48 h ay 10 24 24

40

Time of measurement
20

Fig. 2. Arterial partial pressure of oxygen (PaO2): mean values,

0
Ba se li 30 ne m in 6h 24 h 4 D 8h ay 10 Ba se li 30 ne m in 6h 24 h 4 D 8h ay 10

Time of measurement

95% CIs, minimum and maximum values (whiskers) for the two groups (nebulised corticosteroid [NS] and parenteral corticosteroid [PS]). In a comparison between groups, the differences in percentage change versus baseline values were not significant (p = 0.87, p = 0.32, p = 0.34, p = 0.09 and p = 0.15 at 30 minutes, 6 hours, 24 hours, 48 hours and 10 days, respectively).

Fig. 1. Peak expiratory flow rate (PEFR): mean values, 95% CIs,

minimum and maximum values (whiskers) for the two groups (nebulised corticosteroid [NS] and parenteral corticosteroid [PS]). In a comparison between groups, the differences in percentage change versus baseline values were not significant (p = 0.98, p = 0.43, p = 0.30, p = 0.83 and p = 0.36 at 30 minutes, 6 hours, 24 hours, 48 hours and 10 days, respectively).

SaO2 values during the entire period of assessment (p = 0.75, p = 1.00 and p = 1.00 for PEFR, PaO2 and SaO2, respectively) [figure 1, figure 2 and figure 3].
Clin Drug Invest 2003; 23 (1)

Adis International Limited. All rights reserved.

Nebulised Corticosteroids in COPD

59

NS group
100 90

PS group

80
SaO2 (%)

70 60 50

For PaCO2, there was a decrease in PaCO2 in the PS group by 4.8% compared with baseline, starting at day 2 and continuing to day 10. However, this difference was not statistically significant (figure 4). Similarly, there were changes in pH values compared with baseline of 3.27% in the PS group and 0.1% in the NS group. This difference was also not statistically significant (p = 0.81) [figure 5]. No adverse effects were experienced in either group. Discussion

40
Ba se lin 30 e m in 6h 24 h 4 D 8h ay 10 Ba se lin 30 e m in 6h 24 h 4 D 8h ay 10

Time of measurement

Fig. 3. Arterial oxygen saturation (SaO2): mean values, 95%

CIs, minimum and maximum values (whiskers) for the two groups (nebulised corticosteroid [NS] and parenteral corticosteroid [PS]). In a comparison between groups, the percentage changes versus baseline values were not significant (p = 0.70, p = 0.24, p = 0.12, p = 0.08 and p = 0.31 at 30 minutes, 6 hours, 24 hours, 48 hours and 10 days, respectively).

In our study, it was determined that the effects of parenteral and nebulised corticosteroids were similar both on airway function and on arterial blood gas values. It has been demonstrated that there is inflammation in exacerbations of COPD similar to that in asthma. The increase in number and function of eosinophils is particularly important.[14] Viral infections have been suggested as being responsible
7.6

80

NS group

PS group

NS group

PS group

7.5
PaCO2 (mm Hg)

60

7.4 pH 7.3
40

7.2
20
se lin 30 e m in 6h h h se lin 30 e m in 6h h 48 h ay 10 24 48 10 24 D ay Ba Ba D

7.1
se lin 30 e m in 6h 24 h 4 D 8h ay 10 Ba Ba se lin 30 e m in 6h 24 h 4 D 8h ay 10

Time of measurement

Time of measurement

Fig. 4. Arterial partial pressure of carbon dioxide (PaCO2): mean

values, 95% CIs, minimum and maximum values (whiskers) for the two groups (nebulised corticosteroid [NS] and parenteral corticosteroid [PS]). In a comparison between groups, the differences in percentage change versus baseline values were not significant (p = 0.34, p = 0.75, p = 0.67, p = 0.14 and p = 0.15 at 30 minutes, 6 hours, 24 hours, 48 hours and 10 days, respectively).
Adis International Limited. All rights reserved.

Fig. 5. Arterial pH: mean values, 95% CIs, minimum and maxi-

mum values (whiskers) for the two groups (nebulised corticosteroid [NS] and parenteral corticosteroid [PS]). In a comparison between groups, the differences in percentage change versus baseline values were not significant (p = 0.06, p = 0.33, p = 0.95, p = 0.08 and p = 0.25 at 30 min, 6h, 24h, 48h and at 10 days, respectively).

Clin Drug Invest 2003; 23 (1)

60

Mirici et al.

for the increase in eosinophils in acute exacerbations.[15] Parenteral corticosteroids have been used in acute exacerbations of COPD for a long time.[10] Their use is also recommended in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines as an additional treatment to that with bronchodilators, antibacterials and oxygen. [2] Systemic corticosteroid use in elderly patients with COPD may cause adverse reactions, which may be life-threatening. Although most guidelines recommend oral corticosteroid use in acute axacerbations of COPD, we used intravenous corticosteroids in order to obtain an identical treatment regimen for all patients as some patients were unable to have oral intake or had no possibility of being supplied with an oral drug. In recent years, use of nebulised corticosteroids in both children and adults with acute attacks of asthma has been investigated.[12,13] As nebulised corticosteroids are useful in both stable and acute periods of asthma, they may also be useful in acute exacerbations of COPD. They were found to be effective in a study using nebulised budesonide 2 mg/ml, but a differential diagnosis of patients could not be carried out due to a lack of information about bronchial hyperreactivity of patients before the attack. There are no further studies comparing the effectiveness of nebulised and systemic corticosteroids in acute exacerbations of COPD. In a randomised controlled trial by Morice et al.,[16] it was demonstrated that over the 5 days of the study, the FEV1 increases compared with baseline values between the groups were almost similar, but the biochemical markers associated with corticosteroid adverse effects were better with the nebulised budesonide group than with the corticosteroid group. Similarly, Maltais et al.[17] found that nebulised budesonide had the same effect as oral corticosteroid in the first 72 hours of an acute exacerbation of COPD. In that study, the assessed parameters were change in FEV1 before and after bronchodilator therapy, dyspnoea score, arterial blood gases, duration of hospitalisation and adverse events. The changes in PaO2 and PaCO2 in
Adis International Limited. All rights reserved.

the first 72 hours were significant only in the prednisolone group. In our study, PEFR measurement was used for assessment of airway obstruction. It is known that the correlation between FEV1 and PEFR is not good, but PEFR was used for screening the change in values for patients in our study. All cases had a prior diagnosis of COPD spirometrically. In our study, percentage PEFR values were increased in both the NS and PS groups. Similarly, increases in PaO2 and SaO2 values were also seen in both groups. However, there was no significant difference between the groups, which differs from the study by Maltais et al.[17] In our study, PaCO2 and pH values were significantly different from baseline values in both groups, but the changes between the groups were not different. Maltais et al. in their study found that in the prednisolone group, the proportion of patients showing a substantial decrease in PaCO2 (i.e. 5mm Hg) was significantly larger than in the budesonide or placebo groups. For these reasons, improvement in airway obstruction was similar to that study but the results of blood gas analysis were different from that study. Airway inflammation is an important component of increased airway obstruction. Thus, antiinflammatory treatment seems rational. However, a series of changes affecting the mechanics of breathing and gas exchange occur along with inflammation in acute exacerbations of COPD.[15,18-21] Dynamic hyperinflation and ventilation/perfusion mismatches are also important problems. There is evidence that use of parenteral corticosteroids during attacks decreases airflow resistance and dynamic hyperinflation. However, it is difficult to believe that these outcomes result only from an anti-inflammatory effect. It is possible that the entry of corticosteroids into the bloodstream may affect other tissues as well as the airway mucosa. However, with long-term systemic corticosteroid use, adverse effects on muscles are revealed, and early withdrawal results in recurrences of attacks.[22] This study is the one of the first to compare the efficacy of nebulised corticosteroids with that of
Clin Drug Invest 2003; 23 (1)

Nebulised Corticosteroids in COPD

61

systemic corticosteroids in acute exacerbations of COPD. Efficacy on airway obstruction was found to be similar to that with systemic corticosteroids. However, the observation of a trend to greater efficacy of systemic corticosteroids on arterial blood gas content is interesting. This may result from effects of corticosteroids on other mechanisms involved in gas exchange. The changes in parameters of gas exchange with nebulised budesonide are attributable to its anti-inflammatory effects of decreasing obstruction and decreasing airway resistance, either directly or indirectly. Improvement in airway obstruction would contribute to disappearance of early closing and dynamic hyperinflation. However, the similarity of these effects with nebulised corticosteroids to those with systemic corticosteroids is unclear. Conclusion This study showed that nebulised corticosteroids had similar efficacy to systemic corticosteroids in the treatment of acute exacerbations of COPD. In acute attacks, a nebulised form of corticosteroids is preferable to a systemic form because of fewer adverse effects. However, the effects of nebulised corticosteroids on gas exchange are not clearly understood. These effects may be indirect, since effects on airway inflammation alone cannot be responsible for all events occurring in acute attacks. The effects on gas exchange may be more important in acute attacks, especially for hypercapnoeic attacks. In order to establish the safe use of nebulised corticosteroids in both normocapnoeic and hypercapnoeic exacerbations of COPD, randomised trials in larger groups are needed.

References
1. Turkish Thoracic Society -COPD Study Group. The national guidelines to diagnosis and treatment of chronic obstructive pulmonary disease [in Turkish]. Toraks Dergisi 2000; 1 Suppl. 2: 1-25 2. National Heart, Lung, and Blood Institute. Global initiative for chronic obstructive lung disease. NHLBI Workshop Report 2701; 2001 Apr, Chapter 4 3. ATS Statement. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152: 78-83 4. Jeffery PK. Pathology of asthma and COPD. Eur Respir Rev 1997; 7 (43): 111-8 5. Fabbri LM, Durham S, Holgate ST, et al. Assessment of airway inflammation: an overview. Eur Respir J Suppl 1998 Mar; 26: 6S-8S 6. National Heart, Lung, and Blood Institute. Global Initiative for Asthma. NHLBI/WHO Workshop Report 2002. NIH Publication No: 02-3659. Available from URL: http//www. ginasthma.com/ [Accessed 2002 Jun 10] 7. Turkish Thoracic Society - Asthma Study Group. The national guideline of diagnosis and treatment of asthma [in Turkish]. Toraks Dergisi 2000; 1 Suppl. 1: 1-32 8. Mirici A, Bektas Y, Ozbakis G, et al. Effect of inhaled corticosteroids on respiratory function tests and airway inflammation in stable chronic obstructive pulmonary disease. Clin Drug Invest 2001; 21 (12): 835-42 9. Posthma DS, Kerstjens HAM. Are inhaled glucocorticosteroids effective in chronic obstructive pulmonary disease? Am J Respir Crit Care Med 1999; 160: 66-71 10. Niewoehner D, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1999; 340: 1941-7 11. Sayiner A, Aytemur ZA, Cirit M, et al. Systemic glucocorticosteroids in severe exacerbations of COPD. Chest 2001; 119: 726-30 12. Westbroek J, Saarelainen S, Laher M, et al. Oral steroid-sparing effect of two doses of nebulized fluticasone propionate and placebo in patients with severe chronic asthma. Respir Med 1999; 93: 689-99 13. Winter JH, Dhillon BP, Winter JE, et al. Effect of the early substitution of nebulized fluticasone proprionate 2mg bid for oral prednisolone 50mg in adults during the early recovery period of an acute exacerbation. Eur Respir J 1997; 25 (Suppl): 174s 14. Saetta M. Airway pathology of COPD compared with asthma. Eur Respir Rev 1997; 7 (45): 211-5 15. Calverley PMA, Rennard S, Agusti AGN, et al. Current and future management of acute exacerbations of chronic obstructive pulmonary disease. Eur Respir Rev 1999; 9 (67): 193-205 16. Morice AH, Morris D, Lawson-Matthew P. A comparison of nebulized budesonide with oral prednisolone in the treatment of exacerbations of obstructive pulmonary disease. Clin Pharmacol Ther 1996 Dec; 60 (6): 675-8 17. Maltais F, Ostinelli J, Bourbeau J, et al. Comparison of nebulized budesonide and oral prednisolone with placebo in the treatment of acute exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial. Am J Respir Crit Care Med 2002 Mar 1; 165 (5): 698-703 18. Albert RK, Martin TR, Lewis SW. Controlled clinical trial of methylprednisolone in patients with chronic bronchitis and acute respiratory failure. Ann Intern Med 1980; 92: 753-8

Acknowledgements
The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this study.
Adis International Limited. All rights reserved.

Clin Drug Invest 2003; 23 (1)

62

Mirici et al.

19. Thompson WH, Nielson CP, Carvalbo P, et al. Controlled trial of oral prednisolone in outpatients with COPD exacerbation. Am J Respir Crit Care Med 1996l 154: 407-12 20. Murata GH, Gorby MS, Chick TW. Intravenous and oral corticosteroids for the prevention of relapse after treatment of decompensated COPD: effects on patients with a history of multiple relapses. Chest 2000; 98: 845-9 21. Rubini F, Rampulla C, Nava S. Acute effect of corticosteroids on respiratory mechanics in mechanically ventilated patients with chronic airflow obstruction and acute respiratory failure. Am J Respir Crit Care Med 1994; 149: 306-10

22. Decramer M, Stas K. Corticosteroid-induced myopathy involving respiratory muscles in patients with COPD and asthma. Am Rev Respir Dis 1992; 146: 800-2

Correspondence and offprints: Dr M. Akgun, Atatrk Universitesi, Aziziye Arastirma Hastanesi, Gogus Hastaliklari, Yenisehir Girisi, 25070 Erzurum, Turkey. E-mail: dr_metinakgun@yahoo.com

Adis International Limited. All rights reserved.

Clin Drug Invest 2003; 23 (1)