Comparison of the Efficacy of Nebulised Budesonide With Parenteral Corticosteroids in the Treatment of Acute Exacerbations of Chronic Obstructive Pulmonary Disease

7/30/2019 Comparison of the Efficacy of Nebulised Budesonide With Parenteral Corticosteroids in the Treatment of Acute Exa

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Comparison of the Efficacy of NebulisedBudesonide with Parenteral Corticosteroidsin the Treatment of Acute Exacerbations ofChronic Obstructive Pulmonary Disease

A. Mirici, M. Meral and M. AkgunChest Diseases Department, Faculty of Medicine, Atatrk University, Erzurum, Turkey

Abstract Objective: To compare the efficacy and safety of nebulised budesonide andsystemic corticosteroid in the treatment of acute exacerbations of chronic obstruc-

tive pulmonary disease (COPD).

Design: Randomised, double-blind, placebo-controlled, parallel-group trial.

Patients and interventions: A total of 40 patients who had moderate to severeacute 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 ineither group.

Conclusions: Our study suggests that nebulised budesonide may be an alternative

to parenteral corticosteroids in the treatment of acute exacerbations of COPD.

ORIGINAL RESEARCH ARTICLE Clin Drug Invest 2003; 23 (1): 55-621173-2563/03/0001-0055/$230.00/0 Adis International Limited. All rights reserved.

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 ex-perience 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, forinstance on the use of corticosteroids. Cortico-

steroid use is recommended as an addition to bron-


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pension (Pulmicort Respules/Nebuampul 0.5 mg/ml;

Astra-Zeneca Pharmaceutical Production) and anintravenous placebo (intravenous saline) for 10

days. Budesonide and placebo Respules were

given as 4mg twice daily; prednisolone and pla-

cebo were given once daily intravenously.

All medications and placebo were identical.

Nebulisation procedures were performed by jet

nebuliser (Porta Neb Ventstream 1803; Medic-

Aid) 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 discre-

tion of the admitting physician. Supplementary

oxygen therapy was used to maintain oxygen sat-

uration (SaO2) >90%.

Measurements and Assessments

All patients were hospitalised after baselineevaluations, 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 car-

ried 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 ourclinic (the procedure is not available in our in-

patient 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 meas-

urement 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.

Statistical Analysis

Pearsons chi-square test and the Mann-Whit-ney 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).

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 para-

meters). Changes in pH and PaCO2 values in each

Table I. Comparison of baseline characteristics of the two groups

Characteristic PS group NS group p-Value

Age (y) 64.80 63.06 0.73

Sex (F/M) 5/16 6/13 0.42

Baseline PEFR (%) 32.85 34.32 0.63

Baseline PaO2 (mm Hg) 42.68 44.65 0.60

Baseline PaCO2 (mm Hg) 45.23 40.08 0.14

Baseline SaO2 (%) 75.37 79.74 0.45

Baseline pH 7.359 7.410 0.14

NS = nebulised corticosteroid group; PaCO2 = arterial partial pres-sure of carbon dioxide; PaO2 = arterial partial pressure of oxygen;

PEFR = peak expiratory flow rate; PS = parenteral corticosteroid

group; SaO2 = arterial oxygen saturation.

Nebulised Corticosteroids in COPD 57

Adis International Limited. All rights reserved. Clin Drug Invest 2003; 23 (1)


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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 differencesbetween percentage changes in PEFR, PaO2 and

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].

Table II. Mean values in the groups at different follow-up times

Parameter Baseline 30 min 6h 24h 48h Day 10

PEFR (%)

PS 32.80 37.50 39.50 42.20 45.90 50.65

NS 34.30 36.00 39.81 42.87 48.94 56.69

PaO2 (mm Hg)

PS 42.60 55.06 55.80 58.18 64.75 68.89

NS 44.60 59.81 55.34 57.31 60.55 63.65

PaCO2 (mm Hg)

PS 45.20 42.05 43.15 43.54 41.78 41.70

NS 40.00 39.86 38.82 40.01 40.59 39.68

SaO2 (mm Hg)

PS 75.30 85.75 87.10 88.01 90.41 93.09

NS 79.70 87.71 87.03 88.50 89.26 92.64pH

PS 7.350 7.396 7.394 7.378 7.393 7.392

NS 7.410 7.408 7.420 7.415 7.404 7.411

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.

100

80

60

40

20

0

Baselin

e

30min 6h 24

h48h

Day

10

Baselin

e

30min 6h 24

h48h

Day

10

PEFR(%)

Time of measurement

NS group PS group

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 per-centage 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).

100

80

60

40

20

Baselin

e

30min 6h 24

h48h

Day

10

Time of measurement

NS group PS group

Baselin

e

30min 6h 24

h48h

Day

10

PaO2(mm

Hg)

Fig. 2. Arterial partial pressure of oxygen (PaO2): mean values,95% CIs, minimum and maximum values (whiskers) for the twogroups (nebulised corticosteroid [NS] and parenteral cortico-steroid [PS]). In a comparison between groups, the differences

in percentage change versus baseline values were not signifi-cant (p = 0.87, p = 0.32, p = 0.34, p = 0.09 and p = 0.15 at 30minutes, 6 hours, 24 hours, 48 hours and 10 days, respectively).

58 Mirici et al.



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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. How-

ever, this difference was not statistically signifi-

cant (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

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 inflamma-

tion in exacerbations of COPD similar to that in

asthma. The increase in number and function of

eosinophils is particularly important.[14] Viral in-

fections have been suggested as being responsible

100

90

80

70

60

50

40

SaO2(%)

Baselin

e

30min 6h 24

h48h

Day

10

Baselin

e

30min 6h 24

h48h

Day

10

NS group PS group

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 cortico-steroid [PS]). In a comparison between groups, the percentagechanges 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).

80

60

40

20

Baselin

e

30min 6h 24

h48h

Day

10

Baselin

e

30min 6h 24

h48h

Day

10

PaCO2

(mm

Hg)

NS group PS group

Time of measurement

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

values, 95% CIs, minimum and maximum values (whiskers) forthe two groups (nebulised corticosteroid [NS] and parenteral

corticosteroid [PS]). In a comparison between groups, the dif-ferences in percentage change versus baseline values were notsignificant (p = 0.34, p = 0.75, p = 0.67, p = 0.14 and p = 0.15at 30 minutes, 6 hours, 24 hours, 48 hours and 10 days, respec-tively).

7.6

7.5

7.4

7.3

7.2

7.1

Baselin

e

30min 6h 24

h48h

Day

10

Baselin

e

30min 6h 24

h48h

Day

10

pH

Time of measurement

NS group PS group

Fig. 5. Arterial pH: mean values, 95% CIs, minimum and maxi-mum values (whiskers) for the two groups (nebulised cortico-steroid [NS] and parenteral corticosteroid [PS]). In a comparison

between groups, the differences in percentage change versusbaseline 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).




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for the increase in eosinophils in acute exacerba-

tions.

[15]

Parenteral corticosteroids have been usedin acute exacerbations of COPD for a long time.[10]

Their use is also recommended in the Global Ini-

tiative for Chronic Obstructive Lung Disease

(GOLD) guidelines as an additional treatment to

that with bronchodilators, antibacterials and oxy-

gen.[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 treat-

ment 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 informa-

tion about bronchial hyperreactivity of patients

before the attack.

There are no further studies comparing the

effectiveness of nebulised and systemic cortico-

steroids 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 cortico-

steroid adverse effects were better with the nebul-

ised 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 ad-

verse events. The changes in PaO2 and PaCO2 in

the first 72 hours were significant only in the pred-

nisolone 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 differ-

ence between the groups, which differs from the

study by Maltais et al.[17] In our study, PaCO2 and

pH values were significantly different from base-

line 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 de-

crease in PaCO2 (i.e. 5mm Hg) was significantly

larger than in the budesonide or placebo groups.

For these reasons, improvement in airway obstruc-

tion was similar to that study but the results of

blood gas analysis were different from that study.

Airway inflammation is an important compo-

nent of increased airway obstruction. Thus, anti-

inflammatory treatment seems rational. However,

a series of changes affecting the mechanics of

breathing and gas exchange occur along with in-

flammation 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 cortico-

steroids during attacks decreases airflow resistance

and dynamic hyperinflation. However, it is diffi-

cult 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 at-

tacks.[22]

This study is the one of the first to compare the

efficacy of nebulised corticosteroids with that of

60 Mirici et al.



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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 effi-

cacy 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 obstruc-

tion and decreasing airway resistance, either

directly or indirectly. Improvement in airway

obstruction would contribute to disappearance of

early closing and dynamic hyperinflation. How-

ever, the similarity of these effects with nebulised

corticosteroids to those with systemic corticoste-

roids is unclear.

Conclusion

This study showed that nebulised cortico-

steroids had similar efficacy to systemic cortico-steroids in the treatment of acute exacerbations of

COPD. In acute attacks, a nebulised form of corti-

costeroids 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 at-

tacks. The effects on gas exchange may be more

important in acute attacks, especially for hyper-capnoeic attacks.

In order to establish the safe use of nebulised

corticosteroids in both normocapnoeic and

hypercapnoeic exacerbations of COPD, random-

ised trials in larger groups are needed.

Acknowledgements

The authors have provided no information on sources of

funding or on conflicts of interest directly relevant to the

content of this study.

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Comparison of the Efficacy of Nebulised Budesonide With Parenteral Corticosteroids in the Treatment of Acute Exacerbations of Chronic Obstructive Pulmonary Disease