Oral prednisolone for 4 days does not increase exercise tolerance in men with COPD

Although oral corticosteroids are not recommended in stable chronic obstructive pulmonary disease (COPD), there is evidence of a subjective feeling of well-being among patients with COPD, a term often referred to as steroid euphoria. ¹ This subjective benefit has however not shown to improve the maximal oxygen consumption (VO_2max) in COPD patients. ² One study confirmed the effect of corticosteroids in healthy individuals by administering 60 mg of prednisolone daily for 7 days, showing an increased time to exhaustion (TTE) at 70–75% of VO_2max. ³ The mechanisms might be attributed to an impaired sensation of fatigue, reduced muscle inflammation after exercise or to increased availability of metabolic substrates during exercise (glucose and free fatty acids). ⁴ The aim of this study was to investigate whether 4 days of oral corticosteroids could preserve or increase exercise tolerance and muscle strength in stable COPD patients after performing a fatigue protocol.

The study was a randomized, double-blinded, parallel design with eight participants receiving 37.5 mg of prednisolone and six participants receiving placebo. Approval was obtained from local and national ethics committees (nos H-3-2012-142/ EudraCT 2012-004503-13). The study consisted of six visits: one baseline visit 5–7 days before five consecutive daily visits. At the baseline visit, eligibility was determined, and spirometry, body plethysmography, COPD Assessment Test (CAT), diffusion capacity (D_LCO) and an incremental exercise test were performed. At visit 1, spirometry, CAT and maximal inspiratory/expiratory pressure (MIP/MEP) were assessed followed by a 5-minute warm up at 10% W _max and 20 minutes at 40% W _max. A maximum voluntary contraction (MVC) of the quadriceps muscle on the participant’s leading leg was then followed. After 5 minutes’ recovery, participants performed a submaximal exercise test (SMET) at 70% W _max according to ERS guidelines ⁵ to measure TTE. At visits 2, 3 and 4, participants performed a 5-minute warm up at 10% W _max followed by two constant workload cycling tests at 40% W _max of 20 minutes separated by 4 minutes’ recovery. On visit 5, participants performed the same protocol as on visit 1. At visits 2, 3, 4 and 5, participants were instructed to take the investigated medicinal product 3 hours before the study visit (Figure 1). For the statistical analysis, students t-tests and Mann–Whitney U tests were performed using SPSS (IBM, Version 19.0).

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Figure 1.

Flowchart of the study.

Of the 16 screened patients, 14 were randomized and 2 were excluded. Baseline characteristics are presented in Table 1. Nine patients were on LAMA, two on LABA, nine on LABA/ICS, nine on SABA, two on SAMA/SABA, one on ICS monotherapy, one on phosphodiesterase inhibitors and only one was a current smoker. No difference was found in TTE between the prednisolone and the placebo group p = 0.88 (Table 2), however, both groups showed improvements in TTE from visit 1 to visit 5 (data not shown). For the secondary outcomes, there were no significant changes either except for MVC, which was significantly higher in the prednisolone group (p = 0.03).

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Table 1.

Baseline characteristics of the included patients.

N = 14	Mean	SD
FEV1, l	1.02	0.46
FEV1, %	30.55	12.8
FVC, l	2.44	0.79
FVC, %	56.71	15.29
FEV1/FVC, %	41.49	11.8
RV, l	4.96	1.37
RV, %	201.8	61.7
TLC, l	8.52	1.57
TLC, %	119.4	22.1
RV/TLC, %	57.4	8.3
DLCO SB	4.43	1.48
DLCO VA	0.89	0.30
BMI	23.6	4.8
Pack years	44	18.9
CAT score	14	5.2
Age	62.7	6.71
VO2max	15.86	4.43
W max	75.0	27.6

SD: standard deviation; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; RV: residual volume; TLC: total lung capacity; D_LCO/VA: diffusing capacity of the lung for carbon monoxide/alveolar volume; BMI: body mass index; COPD: chronic obstructive pulmonary disease; CAT: COPD Assessment Test; SB: single breath; VO_2max: maximal oxygen consumption; W _max: maximal work load at the incremental test.

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Table 2.

Results of the primary and secondary outcomes after the study.

Delta values	Prednisolone N = 7	Placebo = 5	p Value
v5–v1	Median [CI 25–75]	Median [CI 25–75]
FEV1, l	−0.01 [0.03; −0.01]	0.0 [−0.5; 0.1]	0.07
FEV1, % predicted	−1.0 [−2.0; 0.0]	0.0 [−1.5; 3.0]	0.18
FVC, l	−0.014 [−0.21; −0.05]	0.15 [−1.0; 0.39]	0.03a
FVC, % predicted	−4.0 [−4.0; −1.0]	3.0 [−2.5; 9.5]	0.03a
MIP	−6.0 [−20.0; −4.0]	5.0 [3.0; 9.5]	0.054
MEP	4.0 [−11.0; 20.0]	−7.0 [−10.0; −3.0]	0.37
CAT	−2 [−3.0; 1.0]	−1.0 [−2.0; 1.5]	0.22
BORG dyspnea	0 [−1.0; 1.0]	0.0 [−1.5; 1.5]	0.95
BORG leg discomfort	1 [0.0; 1.0]	2.0 [3.0; 9.5]	0.83
TTE	51 [−13; 110]	13 [−18; 208]	0.88
MVC	5.15 [3.35; 9.15]	−2 [−5.57; 3.95]	0.03a

CI: confidence interval; FEV₁: forced expiratory volume in 1 second; FVC: forced vital capacity; MIP: maximal inspiratory pressure; MEP: maximal expiratory pressure; COPD: chronic obstructive pulmonary disease; CAT: COPD Assessment Test; TTE: time to exhaustion; MVC: maximal voluntary contraction.

^aSignificant difference between active and placebo group.

The observed improvement in the SMET in this study is probably due to familiarization with the procedure. Accordingly, the TTE on visit 5 might represent the participants’ most accurate exercise tolerance. In previous studies using the SMET, the majority of participants had mild to moderate COPD, ⁵ whereas the patients in this study had very low lung function and were not accustomed to strenuous exercise. Although not powered, the MVC was significantly lower on visit 5 in the placebo group than in the prednisolone group, indicating an increase in muscle strength following the 3 days’ cycling. This finding is in accordance with a previous study. ⁶ Future studies are warranted for evaluation of the effect of short-term systemic corticosteroid in cardiopulmonary measures of strenuous exercise in severe and very severe COPD.