Comparison of two systemic steroid regimens for the treatment of COPD

exacerbations
Yelda Ceviker
1
, Abdullah Sayiner
*
Department of Chest Diseases, Ege University, Faculty of Medicine, Izmir 35100, Turkey
a r t i c l e i n f o
Article history:
Received 4 November 2012
Received in revised form
4 January 2013
Accepted 3 March 2013
Keywords:
Chronic obstructive pulmonary disease
Exacerbation
Systemic glucocorticoid
Treatment
a b s t r a c t
Rationale: Systemic steroids shorten recovery time, improve lung function and hypoxemia in COPD ex-
acerbations. Although several studies have shown that both parenteral and oral steroids are effective and
GOLD guideline recommends use of oral steroids at a dose of 30e40 mg/day, very little data exists as to
whether any route of admininstration (parenteral vs oral) or any dose is more effective and/or safer.
Methods: This was a randomized, parallel-group study aiming to compare the effectiveness and safety of
orally administered lower dose of steroids with parenteral administration of higher doses. Thus, a total of
40 patients were included; one group (Group 1, n 20) received methylprednisolone (MP) as recom-
mended by the GOLD guideline (PO 32 mg/day for seven days) and the other (Group 2, n 20) was given
IV MP at 1 mg/kg/day for four days and 0.5 mg/kg/day for three days.
Results: The two groups were similar with regards to age (69.0 10.5 vs 67.1 8.4 years), duration of
COPD (11.8 8.3 vs 9.7 7.7 years), FEV
1
(41.3 17.3 vs 34.0 12.0%), PaO
2
levels (55.5 9.9 vs
59.1 11.0 mmHg) and dyspnea scores (9.4 1.1 vs 10.0 1.0). Worsening hypercapnic respiratory
failure developed in two patients from Group 1 on days 1 and 2, these were intubated and thus excluded
from the study. At day 7, both groups showed signicant improvements in FEV
1
levels (50.8 19.4 and
43.8 21.4%, respectively) (Table 2), PaO
2
levels (66.5 12.5 and 65.3 10.6 mmHg, respectively)
(Table 3) and dyspnea scores (3,5 2,8 and 4.2 2.8) (Fig. 1). The length of hospital stay was similar for
the two groups (11.0 3.9 vs 12.7 6.4). Regarding adverse events, four patients in Group 1 vs 11
patients in group 2 developed hyperglycemia. Besides, three patients in group 2 had worsening of
previously controlled hypertension. All events were treated and controlled with administration of proper
medications. All patients were followed up for three months. Eight patients in group 1 and 15 patients in
group 2 had unplanned visits to their physicians or to the emergency rooms for recurring exacerbations.
Four patients in group 1 and ve patients in group 2 were readmitted to hospital for recurrence (p NS).
During the follow-up two patients from group 1 died.
Conclusion: These data show that oral administration of MP at a dose 32 mg/day for seven days signif-
icantly improves lung function, symptom scores and oxygenation in patients admitted to the hospital for
COPD exacerbation and is as effective as and possibly safer than parenteral admininistration of higher
doses.
2013 Elsevier Ltd. All rights reserved.
1. Introduction
Exacerbations of COPD are associated with signicant morbidity
and mortality [1e5] and must therefore be promptly and rigorously
treated. Systemic corticosteroids are frequently used in addition to
inhaled bronchodilators in the treatment of COPD exacerbations.
Several randomized controlled trials have shown that their use is
associated with faster improvement in symptoms, airow limita-
tion and oxygenation [6e10]. On the other hand, although guide-
lines recommend the use of 30e40 mg qd for 10e14 days [5], there
is very little data regarding the optimal route of administration
(oral versus parenteral) and the daily dose. In the previous placebo-
controlled trials, the daily dose ranged between 30 mg of pred-
nisolone [8] and 500 mg of methylprednisolone (equivalent to
625 mg of prednisolone) [9] Only one study has been published,
which compared the efcacy of similar doses of prednisolone given
intravenously versus orally [11]. In this latter study, the clinical
outcomes are reported to be similar.
* Corresponding author. Tel.: 90 232 3902905 (ofce), 90 532 6444640
(mobile); fax: 90 232 3887192.
E-mail addresses: yeldaceviker@yahoo.com (Y. Ceviker), abdullah.sayiner@
ege.edu.tr, sayiner2011@gmail.com (A. Sayiner).
1
Dr. Ceviker currently works in the State Hospital, Gumushane, Turkey.
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j ournal homepage: www. el sevi er. com/ l ocat e/ ypupt
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http://dx.doi.org/10.1016/j.pupt.2013.03.004
Pulmonary Pharmacology & Therapeutics xxx (2013) 1e5
Please cite this article in press as: Ceviker Y, Sayiner A, Comparison of two systemic steroid regimens for the treatment of COPD exacerbations,
Pulmonary Pharmacology & Therapeutics (2013), http://dx.doi.org/10.1016/j.pupt.2013.03.004
In this study, we compared the effectiveness and safety of two
systemic steroid regimens: An oral regimenwith xed, lower doses,
as recommended by GOLD statement and a parenteral regimen at
relatively higher doses, determined according to the weight of the
patients. The latter weight-adjusted parenteral regimen has usually
been preferred in our institution because of two concerns. First,
COPD patients are of different phenotypes with signicant differ-
ences in weight and a xed dose may not be suitable for different
individuals. Second, COPD patients with severe exacerbations are
usually hypoxemic and may have right heart failure, both of which
may alter the bioavailability of orally administered drugs. Oral
systemic steroids have only been shown to have good bioavail-
ability in normal volunteers [12]. This study thus aimed to test the
validity of the recommendations of guidelines versus that of our
own clinical approach.
2. Patients and methods
This was a prospective, randomized, single-blind study which
included consecutive COPD patients who were admitted to the
hospital for an exacerbation. The inclusion criteria were age older
than 40 years, previously documented diagnosis of COPD, a smok-
ing history of at least 10 pack-years and the presence of an exac-
erbation, which, in the opinion of the attending physician,
necessitated admission to the hospital. The exclusion criteria were
the presence of pneumonia, uncontrolled hypertension or diabetes
mellitus, previously diagnosed bronchiectasis, need for mechanical
ventilation, use of systemic steroids during the preceding month
and a history of gastrointestinal bleeding during the preceding
three months.
2.1. Study protocol
After obtaining the patients informed consent and recording
their demographic features and the baseline measurements, the
patients were randomized to one of two treatment regimens ac-
cording to a previously prepared randomization list. This list was
kept by one of the investigators (AS), who was also in contact with
the nurses responsible for the treatment of the patients. All patient
interviews and measurements were performed by another inves-
tigator (YC), who remained blinded to the treatment regimens.
The two methylprednisolone treatment regimens were as
follows:
Group 1 received a xed, low-dose oral (MP PO 32 mg/day for 7
days) regimen.
Group 2 received a higher-dose, adjusted to weight, intrave-
nous (MP IV 1 mg/kg qd for 4 days, followed by MP IV 0.5 mg/kg
qd for 3 days) regimen.
All patients received nebulized bronchodilators (salbutamol
2.5 mg and ipratropium 0.5 mg q6h), antibiotics if they met
Anthonisen criteria and nasal oxygen according to the attending
physicians decision.
All patients were hospitalized for at least seven days (during the
treatment period). Following the treatment period, they were dis-
charged according to their attending physicians decision. They
were then followed up for three months.
This study was reviewed and approved by the departments
academic council.
2.2. Measurements
The measurements at admission (baseline) included vital func-
tions (heart rate, blood pressure, respiratory rate), pulmonary
function tests (FVC, FEV1, FEV1/FVC measured using Sensormedics
Vmax 22D spirometer), arterial blood gases (pH, PaO
2
, PaCO
2
,
SaO
2
), biochemical parameters (blood glucose, hepatic and renal
function tests, CRP levels), and symptom scores (shortness of
breath, cough, sputum production measured using visual analog
scores on a 10-point scale). A sputum sample was collected for
bacteriologic analysis.
During the treatment period, the following parameters were
recorded on the respective days:
- Pre and post-bronchodilator spirometry: Days 7, 90
- Arterial blood gases: Days 2, 4, 7, 90.
- Symptom scores: Days 2, 4, 7.
- Adverse events: Daily questioning of the patients and daily
measurements of blood pressure and blood glucose levels
during the treatment period
During the three-month follow-up, all patients were contacted
by phone at the end of the rst and second months and were
questioned about any adverse events, particularly visits to the
emergency room or unplanned visits to their family physicians, use
of antibiotics and/or systemic steroids or admissions to any hos-
pital. At the end of the third month, they were all seen at the
outpatient clinic. At this nal visit, pulmonary function tests,
arterial blood gases, symptom scores, and adverse events were
recorded.
2.3. Statistical analysis
For analyses between groups, the statistical analysis was done
using chi-square test or Fishers exact test for categorical variables,
independent samples t-test for variables with a normal distribution
and Mann Whitney U-test for variables that do not have a normal
distribution. For analyses within groups, paired samples t-test was
used for variables with a normal distribution and Wilcoxon signed-
rank test for variables that do not have a normal distribution.
3. Results
Forty patients were equally randomized to two treatment
groups. The demographic ndings of the patient population are
shown in Table 1. There was no difference between the two groups
on any of the parameters.
There was no difference between the two groups regarding the
percentage of patients with positive sputum cultures (38.9% and
Table 1
Demographic features of the patients.
Group 1 (n 18) Group 2 (n 20)
Age (years) 69.0 10.5 67.1 8.4
Weight (kg) 74.8 10.9 72.5 11.2
Smoking history (pack-years) 56.3 38.8 69.0 38.5
Time since COPD diagnosis (years) 11.8 8.3 9.7 7.7
FEV
1
/FVC (%) 52.2 10.9 53.9 13.4
FVC (ml) (post-bronchodilator) 2170 610 1978 598.7
FVC (%)(post-bronchodilator) 61.8 17.9 54.3 21.7
FEV
1
(ml) (post-bronchodilator) 1115 439.2 958.6 288.3
FEV
1
(%)(post-bronchodilator) 41.3 17.3 34.0 12.0
PaO
2
(mmHg) 55.5 9.9 59.1 11.0
PaCO
2
(mmHg) 36.5 7.8 36.5 10.6
CRP (mg/dl) 7.7 11.9 6.7 10.3
Exacerbations during the preceding year
None 5 8
1e3 10 9
4e6 2 3
7e10 1 0
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Please cite this article in press as: Ceviker Y, Sayiner A, Comparison of two systemic steroid regimens for the treatment of COPD exacerbations,
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45% for Groups 1 and 2, respectively) and the bacteria that grew in
these cultures. Four and ve patients from Group 1 and 2, respec-
tively, did not receive any antibiotics. Similar antibiotics were given
to the other patients (mostly respiratory uoroquinolones and 2nd
and 3rd generation cephalosporins).
3.1. Treatment failures and length of hospital stay
Two patients fromGroup 1 developed severe respiratory failure,
one on day 1 and the other on day 2, and were transferred to the
intensive care unit, intubated and mechanical ventilation was
instituted. They were dropped out from the study. At admission,
their FEV1 levels were 25 and 26% predicted and their PaO2 levels
were 45 and 40 mmHg, respectively. These were two of the four
patients whose initial FEV1 levels were below 30% and PaO2 levels
were equal to or below 45 mmHg.
Two patients in each group received systemic steroids beyond 7
days because of persistence of dyspnea and bronchospasm and
were considered as treatment failures. One of the two patients in
Group 2 developed purulent sputum, culture grew P. aeruginosa
and appropriate antibiotics were initiated. There was no radio-
graphic evidence of pneumonia.
The length of hospital stay was similar for the two groups
(11.0 3.9 vs 12.7 6.4 days).
3.2. Pulmonary function tests
Spirometric measurements obtained at admission and at the end
of the treatment period are shown in Table 2. Both treatment pro-
tocols resulted in signicant improvements in FEV1 and FVC levels.
These improvements were similar in the two treatment groups.
3.3. Arterial blood gases
Both treatment regimens resulted in signicant improvements
in arterial oxygenation. There was no difference between the two
groups regarding the level of improvement (Table 3).
3.4. Symptom scores
Similar improvements were observed with both treatment
regimens in dyspnea (Fig. 1), cough (Fig. 2) and sputum volume
(Fig. 3) scores.
3.5. Follow-up
All patients were followed-up for three months. There was no
signicant difference between Group 1 and 2 in the number of
exacerbations (9 vs 16), unplanned visits to physicians or the
emergency department (8 vs 15), hospitalizations (4 vs 5) and
deaths (2 vs 0, respectively). The causes of death were myocardial
infarction and respiratory failure associated with COPD
exacerbation.
3.6. Adverse events
Hyperglycemia developed in 4 and 11 patients in Groups 1 and
2, respectively. The difference was not statistically signicant. Two
and four patients, respectively, required initiation of insulin ther-
apy. Three patients in Group 2 had worsening of previously
controlled hypertension.
4. Discussion
Although systemic corticosteroids are universally used in the
treatment of moderate-to-severe COPD exacerbations, very little
data exists regarding the optimal regimen. Two previous studies
have shown that the optimal treatment duration is 10e14 days and
that longer treatments do not produce any better clinical results
[9,13]. One other study compared the clinical effectiveness and
safety of oral versus parenteral administration and found similar
improvements in clinical outcomes [11]. There has, however, been
no comparative study that has addressed the optimal dose.
This study has shown that both treatment regimens, i.e.
administration of systemic steroids at a xed, low dose and at a
higher, weight-adjusted dose produce signicant improvements in
airway obstruction, oxygenation and symptom scores and that
similar improvements were obtained with the two regimens. Thus,
in patients with COPD exacerbation that necessitates hospitaliza-
tion, the use of parenterally administered higher doses of systemic
steroids is not warranted. Besides, there was a non-signicant trend
for higher rates of adverse events, namely hypertension and
Table 2
Spirometric measurements at admission and at the end of steroid treatment in the two groups.
Group 1 Group 2
Admission Day 7 Admission Day 7
FVC (ml) (post-bronchodilator) 2170 610 2460 682* 1978 598.7 2186 911**
FVC (%)(post-bronchodilator) 61.8 17.9 71.2 18.1* 54.3 21.7 61.4 29.5**
FEV
1
(ml) (post-bronchodilator) 1115 439.2 1367 618* 959 289 1239 531**
FEV
1
(%)(post-bronchodilator) 41.3 17.3 50.8 19.4* 34.0 12.0 43.8 21.4**
FEV
1
/FVC (%) 52.2 10.9 52.6 14.5 53.9 13.4 53.9 13.6
*Signicantly different than the level at admission (p < 0.05).
**Signicantly different than the level at admission (p < 0.01).
Table 3
Arterial blood gas values at admission and at the end of steroid treatment in the two
groups.
Group 1 Group 2
Admission Day 7 Admission Day 7
PaO
2
(mmHg) 55.5 9.9 66.5 12.5* 59.1 11.0 65.3 10.6*
PaCO
2
(mmHg) 36.5 7.8 35.3 8.5 36.5 10.6 40.8 11.2**
*Signicantly different than the level at admission (p < 0.01).
**Signicantly different than the level at admission (p 0.03).
Admission Day 2 Day 4 Day 7
S
y
m
p
t
o
m

s
c
o
r
e
Group 1
Group 2
Fig. 1. Dyspnea scores of the two treatment groups.
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Please cite this article in press as: Ceviker Y, Sayiner A, Comparison of two systemic steroid regimens for the treatment of COPD exacerbations,
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hyperglycemia, in patients receiving higher doses. In view of the
high prevalence of comorbidities in COPD patients and the addi-
tional negative consequences of such conditions, it appears that the
use of lower doses, as recommended by international guidelines, is
a safer approach.
On the other hand, two patients from the lower-dose group
deteriorated within the rst two days of their hospitalization, had
to be intubated and mechanically ventilated. They had very severe
airowobstruction and much lower PaO
2
levels compared with the
mean level of the study population. As there was no such treatment
failure in the higher-dose group, awaiting further trials, it may be
more prudent to consider parenteral administration of higher doses
in these very severely ill patients.
This study did not have a placebo arm. It is thus difcult to tell
how much of the observed improvements are due to systemic
steroids above the benets obtained from the simultaneously used
bronchodilators. However, the benecial effects of steroids have
been well established by several randomized, placebo-controlled
trials and the addition of a third placebo arm would reduce the
number of patients allocated to each study arm.
Following the establishment of the effectiveness of steroids in
producing faster improvements in lung function and symptom
scores, efforts concentrated on the determination of optimal
treatment protocols. Two studies examined the effects of the
duration of treatment. They have demonstrated that 10e14 days of
treatment is associated with better outcomes compared with
shorter (three-day long) treatments [13], but no additional benets
are obtained with longer (eight-week long) treatment protocols [9].
The only other prospective, placebo-controlled study that
compared the efcacy of similar doses of systemic steroids
administered orally versus parenterally reported similar reductions
in treatment failure rates as well as similar improvements in pul-
monary function and health-related quality of life [11]. Another
retrospective review of a large database has also shown that the
route of administration of systemic steroids is not associated with
any signicant differences in outcomes [14]. These results provide
further support to the recommendation that oral treatment can
safely be used in patients with COPD exacerbations necessitating
admission to the hospital.
These results must be taken into account with caution, because
the study population was relatively small. However, the data on
pulmonary function tests, arterial blood gases and symptom scores
are quite consistent and there does not seem to be a signal which
implies the results could be different in a larger study population.
On the other hand, there was a trend for higher occurrence of hy-
perglycemia and hypertension in patients who were given higher
steroid doses, which might have reached statistical signicance if a
larger group of patients had been studied.
This study was also limited by its single-blinded design. This
stemmed from the fact that no identical-looking placebo medica-
tions could be obtained. However, the physician who interviewed
the patients and obtained the measurements remained blinded,
which, together with the fact that all participants received active
treatment, should have reduced any effect of bias.
Another potential confounder is that there were two variables,
namely the dose and the route of administration, which would
make it difcult to delineate the cause and effect relationship.
However, no signicant differences in the outcomes were detected,
thus this issue does not seem to be of any relevance. As already
stated, the main reason for the choice of the two treatment regi-
mens was to evaluate the effectiveness and safety of the treatment
protocol generally used in our institution in comparison to that of
the regimen recommended by the GOLD statement. Besides, as the
route of administration was already shown not to affect patient
outcomes [11,14], any signicant difference in treatment effects
would possibly be due to the difference in the daily dose. Thus, no
modication was done in the treatment protocols in order to
reduce the number of variables to one.
In summary, these data show that oral administration of
methylprednisolone at a dose 32 mg/day for seven days signi-
cantly improves lung function, symptom scores and oxygenation in
patients admitted to the hospital for COPD exacerbation and is as
effective as and possibly safer than parenteral administration of
higher doses. Further studies are needed in the severely ill patients
in whom there seems to be a higher likelihood of failure.
Acknowledgments
The authors would like to thank Hatice Uluer for her help with
the statistical analyses.
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Pulmonary Pharmacology & Therapeutics (2013), http://dx.doi.org/10.1016/j.pupt.2013.03.004