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pek Ünsal, MD* From the Department of Chest Diseases, Ege University Medical School, Izmir, Turkey.
Correspondence to: Abdullah Sayiner, MD, Ege Üniversitesi Tip Fakültesi, Gö
üs Hastaliklari A.D., Bornova, zmir 35100, Turkey; e-mail: asayiner{at}med.ege.edu.tr
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Design: Prospective, randomized, single-blind study.
Setting: Tertiary-care center.
Patients and methods: Thirty-six patients were included in the study and randomized into two groups: group 1 received MP, 0.5 mg/kg q6h for 3 days, and group 2 was administered the same dosage of MP for the first 3 days, after which it was tapered and terminated on the tenth day. There was no difference between the groups for age, baseline FEV1, PaO2, PaCO2, and pH levels. One patient in group 1 who developed pneumothorax and one patient in group 2 who had steroid-related psychosis could not complete the study.
Results: Both groups showed significant improvements in PaO2 and FEV1 levels, but these were more marked in group 2 (p = 0.012 and p = 0.019, respectively). There was a significant increase in FVC levels in group 2 only (p = 0.003). Group 2 also had a more marked improvement in dyspnea on exertion. There was no difference between the two groups with regards to other parameters, including pH, PaCO2 levels, and other symptom scores. Six patients in group 1 and five patients in group 2 developed new exacerbations within the following 6 months. Hyperglycemia occurred in two patients in each group.
Conclusion: In severe COPD exacerbations, a 10-day course of steroid treatment is more effective than a 3-day course in improving the outcome, but has no benefit in reducing exacerbation rates.
Key Words: COPD • exacerbation • forced expiratory volume • methylprednisolone • steroids
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Five randomized trials have so far been published on the efficacy of systemic corticosteroid treatment in acute exacerbations of COPD using treatment regimens that differed in initial dose (prednisolone, 30 mg/d; prednisone, 60 mg/d; hydrocortisone, 600 mg/d; methylprednisolone [MP], 2 mg/kg/d to 500 mg/d) and duration (3 to 56 days).1 2 3 4 5 These studies1 2 3 4 5 demonstrated that addition of steroids to standard bronchodilator therapy improved airflow and gas exchange, induced a more rapid reduction in dyspnea, and resulted in fewer treatment failures. A 1998 meta-analysis6 of randomized controlled studies, which did not include one of the most recently published studies,5 concluded that steroids were marginally more effective than placebo treatment, in that FEV1 levels improved for the first 3 days only, and significant benefits were observed regarding duration of hospital stay and quality of life. However, out of the seven included studies, two were in abstract form,7 8 and one investigated the efficacy of single-dose steroid treatment during a period of 6 h.9 It is difficult to draw any conclusion from these data as to the optimal dose and treatment duration of systemic steroids used in COPD exacerbations.
This study was undertaken to compare the efficacy of 3-day and 10-day courses of MP for relief of airflow obstruction, improvement in gas exchange, in patients’ symptoms, and recurrent exacerbations during the 6 months after intervention. It also aimed to compare the frequency and seriousness of adverse events occurring during these relatively short-course regimens.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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20 pack-years and severe airway obstruction
(FEV1 < 35% predicted), and who presented with
an exacerbation necessitating hospitalization, were included in the
study. The criteria for admission to the hospital were the presence of
severe dyspnea preventing the patient from performing even minor
activities (getting dressed or eating) and resulting in sleep
disturbances, and the presence of respiratory failure, ie,
PaO2 level 
55 mm Hg
and/or PaCO2 level 45
mm Hg. The exclusion criteria were personal or family history of
asthma, atopy, allergic disease, presence of eosinophilia, use of
systemic steroids within the preceding month, presence of severe
hypertension, uncompensated congestive heart failure or uncontrolled
(or difficult to control) diabetes mellitus, and respiratory failure
necessitating mechanical ventilation therapy. All patients gave written
informed consent.
Study Protocol
COPD patients who met the inclusion criteria were randomly
assigned to one of two treatment groups: group 1 received MP, 0.5 mg/kg
IV q6h for 3 days, followed by normal saline solution as placebo
treatment IV twice daily for the following 3 days and once daily for
the final 4 days. Group 2 received the same dose of MP for the first 3
days, followed by 0.5 mg/kg q12h for 3 days and 0.5 mg/kg/d for 4 more
days (total 10 days).
The randomization code was set up and sealed envelopes were prepared before the study initiation by one of the authors (A.S.), who also prepared the study medications with the head nurse. The patients were blinded to the nature of the IV medications. On inclusion of a patient into the study, the related envelope was opened and the drug package was given to the nurse in charge of the treatment.
All patients remained hospitalized for at least 10 days, during which the study treatment continued and measurements were obtained. They were all given high doses of inhaled ß2-agonists, ipratropium bromide, theophylline (dose determined according to serum level measurements), antibiotics when indicated (presence of increased dyspnea, sputum volume and sputum purulence),10 and H2-receptor antagonists for 10 days, during which they received the study medication.
Study End Points
The primary end points were FEV1 and
PaO2 levels on day 3 and day 10. The
former was measured with a portable spirometer (Spirobank; Medical
International Research; Rome, Italy) every morning at 8
AM after the patients had received their morning
medications. The spirometry was performed by one of three investigators
(Z.A.A., M.C., I.U.). The best of three measurements was recorded. All
tests were performed using the same individual device, which was
calibrated each study day. Arterial blood gas levels were determined at
admission and on day 1, day 3, day 5, day 7, and day 10. Blood samples
were obtained while the patients were breathing room air (30 min after
cessation of supplemental oxygen, if the patient was receiving oxygen
on the day of evaluation).
The secondary end points were symptom scores (dyspnea, cough), recurrence of exacerbation in the following 6 months, and adverse events. Symptom scores were obtained by asking the patients to rate their physical and emotional function on a 7-point scale, in which higher scores represented better function. For the most part, the patients filled in the questionnaires personally; however, 13 patients (8 from group 1 and 5 from group 2) could not respond on their own because they had too much difficulty in reading and writing. In that case, they were interviewed by a nurse who was uninformed about the medication given.
On discharge from the hospital, all patients were asked to report to the outpatient clinic if they had recurrent exacerbation, ie, worsening or reappearance of their symptoms (mainly, shortness of breath, cough, sputum production, and/or wheeze). The physicians at the outpatient clinic were blinded to the treatment regimen the patients had been assigned. The data on recurrences were collected by reviewing the patients’ records.
The statistical analysis was performed with analysis of variance using a two-factor experiment model with a repeated measure on one factor (time). For parameters found to be significant with this test, student’s paired t test with Bonferroni correction was performed in order to determine at which study phase (between days 0 to 3, or days 3 to 10) there was a significant difference. All data are expressed as mean ± SEM.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One patient in group 1 developed pneumothorax and pneumomediastinum on day 2 and was transferred to the ICU for worsening respiratory and hemodynamic status. One patient in group 2 developed steroid-related psychosis on day 4. His symptoms disappeared after the glucocorticoid treatment was stopped. Both patients were excluded from the study. Thus, data from 34 patients were evaluated in this analysis.
Demographic findings of the study population are presented in Table 1 . Only 2 of 36 patients were female, reflecting the male dominance of the smoking adult population and the current epidemiology of COPD in Turkey.
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All patients, except for one, recovered from their exacerbation and were discharged from the hospital after they completed the study on day 10. One patient in group 1 showed no objective sign of improvement until day 10, and open-label steroid treatment was started thereafter. No other patient required any additional treatment.
Arterial Blood Gases
Both groups showed significant improvements in
PaO2, but this was more marked in
group 2 (p = 0.012; Fig 1
). Analysis of the data revealed that only group 2 improved further
between day 3 and day 10 (p < 0.01; Table 2
). There was no change in PaCO2 levels
in either group through the 10-day period. The pH levels normalized in
both groups (p < 0.01), without there being any difference between
the two groups.
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Symptom Scores
Both groups showed significant improvements in all symptom scores,
including shortness of breath at daytime, at night, and on exertion;
cough; and sputum volume. However, the improvement in dyspnea on
exertion observed in group 2 was significantly better than that
obtained in group 1 (p = 0.024; Table 3
). This was associated with the fact that, although both groups had
similar increases in this symptom score at day 3, further significant
improvement occurred between day 3 and day 10 in group 2 only
(p < 0.01).
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Patients were followed up for 6 months after discharge from the hospital. In group 1, eight exacerbations recurred in six patients, whereas five patients in group 2 each developed one exacerbation. The difference in the rate of recurrences was not significant.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A comparison of 3 days and 10 days of treatment was chosen for the two groups because these times were roughly the treatment durations of the previous studies showing that steroids were effective. Besides, both regimens were of relatively short duration, taking into account the potential for adverse events.
This study can be criticized for the fact that the duration of hospitalization was not included as an end point. Instead, the patients remained in the hospital throughout the 10-day period according to the protocol. This was both to ensure that all airflow measurements were performed with adequate technique, using the same apparatus, and to avoid the risk of losing patients to follow-up. The latter reason derives from the fact that the majority of the patients have functional and economical limitations for frequent visits to the hospital. Even when they are not included in such studies, it is the general policy at this center to hospitalize those with respiratory failure and severe disability for prolonged periods.
Another criticism may arise regarding the use of a portable spirometer, which is known to be less accurate than the larger, mechanical dry rolling seal spirometers. The only reason for this choice was that the pulmonary function tests laboratory of this center is situated at the outpatient clinic, away from the patient wards, and transfer of these severely disabled patients for frequent measurements was judged to be difficult, if not unethical. We tried to compensate for this shortcoming by using the same apparatus at all occasions and by frequent calibrations.
Our data showed that glucocorticoid treatment together with the optimal bronchodilator therapy resulted in more marked improvements in PaO2, FVC, and FEV1 levels in COPD patients who were administered systemic steroids for 10 days as compared to 3 days. Similarly, the patients given the 10-day treatment had better symptom scores for dyspnea on exertion than those receiving the shorter-course therapy.
Thus, extending steroid therapy to 10 days provides a higher level of improvement. Whether a 10-day course is the optimal duration of therapy cannot be determined by the present data, but the results of the recent multicenter, Veterans Affairs study5 showed that a 2-week MP regimen was effective as an 8-week treatment. Other studies using similar steroid doses for 8 to 14 days also reported significant improvements in airway obstruction levels, symptom scores, and fewer recurrences at the end of 2-week follow-up periods, as compared to patients treated with bronchodilators only.2 3 4 The two placebo-controlled studies7 8 that used similar glucocorticoid regimens but reported no benefit either suffered from high dropout rates (20% and 43%, respectively) or presented data obtained at the end of a 1-month follow-up period only.7
Levels of FVC and FEV1 at day 3 appeared to have improved more in group 2 than in group 1, a finding for which there is no straightforward explanation with the available data. The two groups were found to have similar characteristics, including blood eosinophilia, and efforts were made to exclude patients with asthmatic features. However, there might have been differences in sputum eosinophilia, a parameter that was not examined. It has previously been shown11 that sputum eosinophilia, but not blood eosinophilia, was a predictor of benefit from prednisone in patients with stable COPD. Besides, another study12 found that the percentage of eosinophils in sputum was significantly increased in bronchitis during exacerbations compared with that in stable bronchitis, but there was considerable interindividual variability. Further work is thus needed to determine the potential predictors of response to steroids in COPD exacerbations and to assess the value of examining sputum for eosinophilia in this setting.
In this study, although more marked improvements were observed in patients administered a 10-day course of steroids (in oxygenation level, airflow obstruction, and symptom scores), these improvements did not seem to translate into fewer exacerbations in the following 6 months. The only study5 with a long-term follow-up period showed that the early benefit was associated with fewer treatment failures at 3 months, but not at 6 months.
These data suggest that a 10-day course of systemic glucocorticoids is more effective than a 3-day course, in that it provides more marked objective and subjective improvements at short term, and that adverse events are rare; however, a 10-day course offers limited, if any, advantage in reducing exacerbation rates.
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Acknowledgements |
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Footnotes |
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Received for publication November 12, 1999. Accepted for publication October 11, 2000.
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References |
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This article has been cited by other articles:
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  S. F. Vondracek and B. A. Hemstreet Retrospective evaluation of systemic corticosteroids for the management of acute exacerbations of chronic obstructive pulmonary disease Am. J. Health Syst. Pharm., April 1, 2006; 63(7): 645 - 652. [Abstract] [Full Text] [PDF]
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 J. F. Donohue and J. A. Ohar Effects of Corticosteroids on Lung Function in Asthma and Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2004; 1(3): 152 - 160. [Abstract] [Full Text] [PDF]
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 J. M. Singh, V. A. Palda, M. B. Stanbrook, and K. R. Chapman Corticosteroid Therapy for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Systematic Review Arch Intern Med, December 9, 2002; 162(22): 2527 - 2536. [Abstract] [Full Text] [PDF]
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 B. Novak The Role of Corticosteroids in Acute Exacerbations of Chronic Obstructive Pulmonary Disease Crit. Care Nurse, October 1, 2002; 22(5): 80 - 81. [Full Text] [PDF]
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 J. K. Stoller Acute Exacerbations of Chronic Obstructive Pulmonary Disease N. Engl. J. Med., March 28, 2002; 346(13): 988 - 994. [Full Text] [PDF]
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