Recommendation of the use of systemic steroids in chronic obstructive disease (COPD) exacerbation rely on trials that excluded patients requiring ventilatory support. In an open-label, randomised evaluation of oral prednisone administration, 217 patients with acute COPD exacerbation requiring ventilatory support were randomised (with stratification on the type of ventilation) to usual care (n=106) or to receive a daily dose of prednisone (1 mg·kg(-1)) for up to 10 days (n=111). There was no difference regarding the primary end-point, intensive care unit mortality, which was 17 (15.3%) deaths versus 15 (14%) deaths in the steroid-treated and control groups, respectively (relative risk 1.08, 95% CI 0.6-2.05). Analysis according to ventilation modalities showed similar mortality rates. Noninvasive ventilation failed in 15.7% and 12.7% (relative risk 1.25, 95% CI 0.56-2.8; p=0.59), respectively. Both study groups had similar median mechanical ventilation duration and intensive care unit length of stay, which were 6 (interquartile range 6-12) days versus 6 (3.8-12) days and 9 (6-14) days versus 8 (6-14) days, respectively. Hyperglycaemic episodes requiring initiation or alteration of current insulin doses occurred in 55 (49.5%) patients versus 35 (33%) patients in the prednisone and control groups, respectively (relative risk 1.5, 95% CI 1.08-2.08; p=0.015). Prednisone did not improve intensive care unit mortality or patient-centred outcomes in the selected subgroup of COPD patients with severe exacerbation but significantly increased the risk of hyperglycaemia.
RATIONALE: Systemic steroids shorten recovery time, improve lung function and hypoxemia in COPD exacerbations. 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 30-40 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 recommended 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), FEV1 (41.3 ± 17.3 vs 34.0 ± 12.0%), PaO2 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 significant improvements in FEV1 levels (50.8 ± 19.4 and 43.8 ± 21.4%, respectively) (Table 2), PaO2 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 five 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 significantly 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.
PURPOSE: The objective of this study is to evaluate the effectiveness and safety of nebulized glucocorticoids therapy for AECOPD, with systemic administration of glucocorticoids and placebo as control. METHODS: This was a multi-center, randomized, double blind, double dummy and parallel controlled trial. AECOPD patients were randomly assigned into BUD group (n=53, nebulized budesonide 2mg/4ml, q6h and normal saline (NS) 10ml iv qd or MP group (n=54, methylprednisolone 40mg, iv and nebulized NS 4ml q6h, or placebo group (n=46, nebulized NS 4ml q6h and NS 10ml iv qd) for 7 days. RESULTS: The number of withdraw rate due to treatment failair was significantly higher in placebo group than in BUD and MP groups (p=0.005). The average improvement of FEV1 after 72 hours of treatment in the BUD group and MP group were 140ml (increased 22.9% from baseline) and 190 ml (25.7%), respectively, which were significantly higher than in the placebo group 110ml (15.2%). 7 days after treatment, FEV1 improvement in the BUD group (230ml, 33.3%) was the greatest among the 3 groups. Shortness of breath was significantly alleviated in all of the 3 groups, with better improvement in the BUD group and the MP group than in the placebo group (p<0.05). Use of rescue medication and systemic glucocorticoids, and number of hospitalization days were similar among the 3 groups. The incidence of adverse events of the 3 groups were 11.3%, 8.9% and 10.9%. 10.4% of the patients in the BUD group experienced blood glucose elevation, and 6.5% of the patients in the MP group had the same experience. CONCLUSIONS: Nebulized glucocorticoids and intravenous glucocorticoids were better than placebo in improving pulmonary function and releasing shortness of breath. Though the percentage of adverse events in the 3 groups remained similar, further investigation to the effect of both corticosteriod therapies on blood glucose is necessary. CLINICAL IMPLICATIONS: Nebulized glucocorticoids therapy could be an option for the treatment of AECOPD. It was as effective as sytematic administration of corticosteriods.
BACKGROUND: Randomized trials assessing the effect of systemic corticosteroids on chronic obstructive pulmonary disease (COPD) exacerbations excluded patients who were mechanically ventilated or admitted to the intensive care unit (ICU). Critically ill patients constitute a population of persons who are prone to develop complications that are potentially associated with the use of corticosteroids (eg, infections, hyperglycemia, ICU-acquired paresis) that could prolong the duration of mechanical ventilation and even increase mortality.
METHODS: A double-blind placebo-controlled trial was conducted to evaluate the efficacy and safety of systemic corticosteroid treatment in patients with an exacerbation of COPD who were receiving ventilatory support (invasive or noninvasive mechanical ventilation). A total of 354 adult patients who were admitted to the ICUs of 8 hospitals in 4 countries from July 2005 through July 2009 were screened, and 83 were randomized to receive intravenous methylprednisolone (0.5 mg/kg every 6 hours for 72 hours, 0.5 mg/kg every 12 hours on days 4 through 6, and 0.5 mg/kg/d on days 7 through 10) or placebo. The main outcome measures were duration of mechanical ventilation, length of ICU stay, and need for intubation in patients treated with noninvasive mechanical ventilation.
RESULTS: There were no significant differences between the groups in demographics, severity of illness, reasons for COPD exacerbation, gas exchange variables, and corticosteroid rescue treatment. Corticosteroid treatment was associated with a significant reduction in the median duration of mechanical ventilation (3 days vs 4 days; P = .04), a trend toward a shorter median length of ICU stay (6 days vs 7 days; P = .09), and significant reduction in the rate of NIV failure (0% vs 37%; P = .04).
CONCLUSION: Systemic corticosteroid therapy in patients with COPD exacerbations requiring mechanical ventilation is associated with a significant increase in the success of noninvasive mechanical ventilation and a reduction in the duration of mechanical ventilation.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01281748.
The present study was designed to evaluate the hypothesis that nebulised budesonide (NB) might be an alternative to systemic corticosteroids (SC) in the treatment of patients with exacerbations of chronic obstructive pulmonary disease (ECOPD). Patients hospitalised with ECOPD (n = 159) were randomised into three groups. Group 1 received only standard bronchodilator treatment (SBDT), group 2 received SC (40 mg prednisolone) plus SBDT, and group 3 received NB (1,500 microg q.i.d.) plus SBDT. Improvement during 10-day hospitalisation was compared with exacerbation and rehospitalisation rates after discharge. While mean+/-sd age was 64.1+/-8.9 yrs (female/male = 0.1), mean forced expiratory volume in one second (FEV(1)) at admission was found to be 37.2+/-12.2% predicted. Arterial blood gases and spirograms recovered faster in groups 2 and 3. While improvements in arterial oxygen tension (P(a,O(2))) and forced vital capacity (FVC) in group 2, and improvements in P(a,O(2)), FVC and FEV(1) in group 3, became significant at 24-h control, the first significant improvement in group 1 appeared in arterial oxygen saturation at 72-h control. The mean improvement of P(a,O(2)) after 10 days was 1.20 and 1.06 kPa (9 and 8 mmHg) higher in group 2 and 3, respectively, than in group 1. Blood glucose exhibited an upward trend only in group 2. The study demonstrates that nebulised budesonide may be an effective and safe alternative to systemic corticosteroids in the treatment of exacerbations of chronic obstructive pulmonary disease.
Background: Treatment with systemic corticosteroids for exacerbations of COPD results in improvement in clinical outcomes. On hospitalization, corticosteroids are generally administered IV. It has not been established whether oral administration is equally effective. We conducted a study to demonstrate that therapy with oral prednisolone was not inferior to therapy with IV prednisolone using a double-blind, double-dummy design. Methods: Patients hospitalized for an exacerbation of COPD were randomized to receive 5 days of therapy with prednisolone, 60 mg IV or orally. Treatment failure, the primary outcome, was defined as death, admission to the ICU, readmission to the ICU because of COPD, or the intensification of pharmacologic therapy during a 90-day follow-up period. Results: A total of 435 patients were referred for a COPD exacerbation warranting hospitalization; 107 patients were randomized to receive IV therapy, and 103 to receive oral therapy. Overall treatment failure within 90 days was similar, as follows: IV prednisolone, 61.7%; oral prednisolone, 56.3% (one-sided lower bound of the 95% confidence interval [CI], -5.8%). There were also no differences in early (ie, within 2 weeks) treatment failure (17.8% and 18.4%, respectively; one-sided lower bound of the 95% CI, -9.4%), late (ie, after 2 weeks) treatment failure (54.0% and 47.0%, respectively; one-sided lower bound of the 95% CI, -5.6%), and mean (± SD) length of hospital stay (11.9 ± 8.6 and 11.2 ± 6.7 days, respectively). Over 1 week, clinically relevant improvements were found in spirometry and health-related quality of life, without significant differences between the two treatment groups. Conclusion: Therapy with oral prednisolone is not inferior to IV treatment in the first 90 days after starting therapy. We suggest that the oral route is preferable in the treatment of COPD exacerbations. Trial registration: Clinicaltrials.gov Identifier: NCT00311961.
FROM THE AUTHORS: We have read with interest the letter concerning our manuscript recently published in the European Respiratory Journal [1] and appreciate the concerns raised by A. Singh. Underlining chronic obstructive pulmonary disease (COPD) as a systemic disorder has gained wide acceptance among pulmonary physicians. The main evidence supporting this approach is the increased levels of systemic inflammatory markers (tumour necrosis factor-a, C-reactive protein and interleukins) and the presence of cachexia and muscle weakness/wasting [2, 3]. It is not yet known what kind of extrapulmonary problems these increased inflammatory markers indicate or give rise to. They have been shown to be strongly related to the level of inflammation in the lungs, and do not seem to indicate any kind of abnormal systemic process independent of the pathology within the lungs of COPD patients [4]. Cachexia and muscle weakness/wasting mainly occur due to the increased work of breathing, decreased appetite and avoidance of eating behavior due to increased breathlessness in COPD patients. It is still not clear which potential systemic abnormalities occurring during exacerbations of COPD (ECOPD) may be relieved by systemic corticosteroid administration alone. Therefore, from a practical point of view, we are not yet convinced that there is a significant difference between treating COPD as a systemic or local disease. Secondly, the rationale of high-dose nebulised corticosteroid administration in severe COPD is the same as that for the administration of systemic corticosteroids. No published data currently exist that directly test the efficacy of systemic corticosteroid administration and the severity of COPD exacerbation according to dominant cell type in the lower airways. Nebulised corticosteroid administration has the advantage of enabling the clinician to avoid the systemic side-effects of corticosteroids. Thirdly, it is difficult to discuss the response to high-dose nebulised corticosteroid administration according to the cause of exacerbation and the dominant cell type in any specific cause of exacerbation, due to a lack of any published data. These issues were not addressed in our study. However, it must be remembered that since patients were randomly included in our study, there should be no difference between the groups with respect to the cause of exacerbation and dominant cell type in the lower airways. The important point here is that we did not find any difference between the efficacies of high-dose nebulised budesonide and systemic corticosteroid administration, with a lower side-effect profile in the nebulised corticosteroid arm. We agree with A. Singh that 10% of patients with COPD have some characteristics of asthma, and their response to the high-dose nebulised budesonide may potentially differ from that of other COPD patients. However, these patients were not excluded or were not separately evaluated in our study. We believe that if any COPD patients with asthmatic features were included in our study, they did not have significant impact on the results as they were randomly distributed among the groups. Although there are a limited number of studies regarding the clinical efficacy of nebulised corticosteroids in exacerbations of bronchial asthma and COPD [5–10]; the majority indicate a positive opinion on their use. However, due to the differences in study design, study population, drug dosages and followup periods, these previous studies are almost incomparable. Before drawing any firm conclusions, the results of large multicentre randomised clinical trials should be awaited. The dosages used to test the clinical efficacy of high-dose nebulised corticosteroids in patients with ECOPD and asthma are very low compared with systemic corticosteroid doses (1– 8 mg?day-1 versus 30–60 mg?day-1, respectively). Moreover, there is very little systemic absorption of inhaled/nebulised corticosteroids. For these reasons, it seems very difficult to attribute any of the positive or negative systemic effects to the short-term nebulised corticosteroid use. Finally, a large percentage of chronic obstructive pulmonary disease patients hospitalised with exacerbations of chronic obstructive pulmonary disease have received treatment with high-dose inhaled corticosteroids (1,000–2,000 mg?day-1) prior to exacerbation and hospitalisation. Administration of a similar dose of nebulised corticosteroid during an exacerbation does not sound reasonable to the current authors. We believe that higher doses of corticosteroids should be tested to determine their efficacy in patients hospitalised with exacerbations of chronic obstructive pulmonary disease.
BACKGROUND: Patient-reported outcomes (PRO) questionnaires are being increasingly used in COPD clinical studies. The challenge facing investigators is to determine what change is significant, ie what is the minimal clinically important difference (MCID). This study aimed to identify the MCID for the clinical COPD questionnaire (CCQ) in terms of patient referencing, criterion referencing, and by the standard error of measurement (SEM).
METHODS: Patients were > or = 40 years of age, diagnosed with COPD, had a smoking history of >10 pack-years, and were participating in a randomized, controlled clinical trial comparing intravenous and oral prednisolone in patients admitted with an acute exacerbation of COPD. The CCQ was completed on Days 1-7 and 42. A Global Rating of Change (GRC) assessment was taken to establish the MCID by patient referencing. For criterion referencing, health events during a period of 1 year after Day 42 were included in this analysis.
RESULTS: 210 patients were recruited, 168 completed the CCQ questionnaire on Day 42. The MCID of the CCQ total score, as indicated by patient referencing in terms of the GRC, was 0.44. The MCID of the CCQ in terms of criterion referencing for the major outcomes was 0.39, and calculation of the SEM resulted in a value of 0.21.
CONCLUSION: This investigation, which is the first to determine the MCID of a PRO questionnaire via more than one approach, indicates that the MCID of the CCQ total score is 0.4.
Recommendation of the use of systemic steroids in chronic obstructive disease (COPD) exacerbation rely on trials that excluded patients requiring ventilatory support. In an open-label, randomised evaluation of oral prednisone administration, 217 patients with acute COPD exacerbation requiring ventilatory support were randomised (with stratification on the type of ventilation) to usual care (n=106) or to receive a daily dose of prednisone (1 mg·kg(-1)) for up to 10 days (n=111). There was no difference regarding the primary end-point, intensive care unit mortality, which was 17 (15.3%) deaths versus 15 (14%) deaths in the steroid-treated and control groups, respectively (relative risk 1.08, 95% CI 0.6-2.05). Analysis according to ventilation modalities showed similar mortality rates. Noninvasive ventilation failed in 15.7% and 12.7% (relative risk 1.25, 95% CI 0.56-2.8; p=0.59), respectively. Both study groups had similar median mechanical ventilation duration and intensive care unit length of stay, which were 6 (interquartile range 6-12) days versus 6 (3.8-12) days and 9 (6-14) days versus 8 (6-14) days, respectively. Hyperglycaemic episodes requiring initiation or alteration of current insulin doses occurred in 55 (49.5%) patients versus 35 (33%) patients in the prednisone and control groups, respectively (relative risk 1.5, 95% CI 1.08-2.08; p=0.015). Prednisone did not improve intensive care unit mortality or patient-centred outcomes in the selected subgroup of COPD patients with severe exacerbation but significantly increased the risk of hyperglycaemia.
