Accepted Manuscript

Impact of resistance training in chronic obstructive pulmonary disease patients during

periods of acute exacerbation

Rodrigo Cerqueira Borges , MSc Celso R.F. Carvalho , PhD

PII: S0003-9993(14)00399-2
DOI: 10.1016/j.apmr.2014.05.007
Reference: YAPMR 55843

To appear in: ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION

Received Date: 29 July 2013

Revised Date: 26 March 2014
Accepted Date: 9 May 2014

Please cite this article as: Borges RC, Carvalho CRF, Impact of resistance training in chronic obstructive
pulmonary disease patients during periods of acute exacerbation, ARCHIVES OF PHYSICAL
MEDICINE AND REHABILITATION (2014), doi: 10.1016/j.apmr.2014.05.007.

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Running title: Resistance training in hospitalized COPD

Impact of resistance training in chronic obstructive pulmonary disease patients during periods

of acute exacerbation

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Rodrigo Cerqueira Borges1,2, MSc (rodrigounopar@yahoo.com.br)

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Celso R. F. Carvalho1, PhD (cscarval@usp.br)

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1Physical Therapy Department, School of Medicine, University of São Paulo, São Paulo,

Brazil
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1,2 University Hospital, University of São Paulo, São Paulo, Brazil

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Correspondence should be addressed to:

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Rodrigo Cerqueira Borges

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Rua Trajano Reis 777 apto 34 C1

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São Paulo, SP, Brazil

CEP: 05541030

Phone: +55-11-25392965; FAX: +55-11-3085-0992

Email: rodrigounopar@yahoo.com.br
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Mr. Borges has no conflicts of interest to disclose

Dr. Carvalho has no conflicts of interest to disclose

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Grants support: This study was supported by grants 2007/51-354-7, São Paulo Research

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Foundation (FAPESP) and Conselho Nacional Pesquisa (CNPq), Brazilian Scientific

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Foundations.

ClinicalTrials.gov identifier: NCT01786928

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1 Impact of resistance training in chronic obstructive pulmonary disease patients during

2 periods of acute exacerbation

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5 ABSTRACT

6 Objective: To evaluate the effects of whole-body resistance training on exercise capacity,

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7 health-related quality of life (HRQL) and muscle strength in patients hospitalized for

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8 exacerbation of chronic obstructive pulmonary disease (COPD).

9 Design: A randomized controlled trial.

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10 Setting: Ward of a University Hospital.
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11 Participants: Forty-six patients were randomized to either control (CG) or training (TG)

12 groups and 29 completed the study.

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13 Interventions: The training consisted of weight lifting exercises for 6 muscle groups in the
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14 upper and lower limbs (2 sets of 8 repetitions each) and initial load was set at 80% of the 1-
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15 repetition maximum load.

16 Main Outcome Measure(s): Patients were evaluated on the 2nd day of hospitalization, at
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17 hospital discharge and 30 days post-discharge. Patients were evaluated on the basis of the six-

18 minute walking distance (6MWD), HRQL, muscle strength, systemic inflammatory markers
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19 and the level of physical activity in daily life (PADL).

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20 Results: CG showed a reduction in the strength of lower limb muscles (p<0.05) but not in the

21 6MWD (p>0.05). In contrast, patients from TG improved the strength in the lower limb

22 muscles and 6MWD during and 30 days after hospitalization (p<0.05). TG also improved the

23 impact domain in the HRQL after hospitalization. No improvement in PADL was observed in

24 the TG. Finally, a reduction in the blood levels of inflammatory markers was observed only

25 in the TG after hospitalization.

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26 Conclusions: Our results suggest that resistance training during hospitalization improves

27 6MWD, HRQL and lower limb muscle strength and without altering the levels of systemic

28 inflammation. However, future research should explore this intervention in larger randomized

29 trials.

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30 Keywords: resistance training; quality of life; hospitalization; chronic obstructive pulmonary

31 disease

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32

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33 LIST OF ABBREVIATIONS

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36 AE acute exacerbation

37 COPD chronic obstructive pulmonary disease

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38 HRQL health-related quality of life

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39 PADL physical activity in daily life

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40 6MWD six-minute walking distance

41 PR pulmonary rehabilitation
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42 WBRT whole-body resistance training

43 ICU intensive care unit

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44 IL interleukin
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45 TNF-α tumor necrosis factor-α

46 CRP C-reactive protein

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51 INTRODUCTION

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54 Acute exacerbation (AE) is common in chronic obstructive lung disease (COPD) patients and

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55 cause specific symptoms, such as changes in baseline dyspnea, cough and/or expectoration

56 beyond the daily variations in symptoms, which are sufficient to justify a change in

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57 treatment1. With disease progression, exacerbations become more frequent and have negative

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58 impacts on pulmonary function2, health status3 and health-related quality of life (HRQL)1.

59 Commonly, severe exacerbations lead to reduced muscle strength4 and exercise capacity5 and

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60 often require patient hospitalization1, which results in large health expenditures. Previously, it
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61 was demonstrated that patients sustain a great loss in exercise capacity after an exacerbation

62 that is not recovered, even after improvement in the patients’ symptoms and lung function5.
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63 This loss is a concern because lower exercise capacity has been shown to be a predictor of

rehospitalization6 and survival in COPD patients7. Although various mechanisms may

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contribute to the decrease in exercise capacity during AE of COPD8, it seems that muscle
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66 dysfunction plays an important role because a reduction in exercise capacity has been shown
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67 to be strongly associated with musculoskeletal dysfunction9-10.

68
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69 The effectiveness of pulmonary rehabilitation (PR) strategies to counteract these

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70 musculoskeletal dysfunction are widely known and there is a large body of evidence

71 demonstrating the benefits in stable COPD patients1. Currently, the ideal timing for the onset

72 of PR and the effectiveness of different rehabilitation strategies during and/or immediately

73 after the acute phase of the exacerbation8,11 has been discussed. Some studies12,13 have

74 investigated a combination of PR programs during and after exacerbation and to the best of
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75 our knowledge only few studies have investigated the benefits during hospitalization14,15;

76 therefore, the effect these strategies exercises in patients for unstable COPD remain uncertain.

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78 Resistance training has been shown to be a therapeutic option for preventing and/or reversing

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79 muscular dysfunction due to immobility in healthy subjects16 and stable COPD patients17 by

80 inducing hypertrophy of type II fibers18 and increasing muscle strength and exercise

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81 capacity19. In addition, less dyspnea is reported with resistance training compared with other

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82 exercise modalities20. Recently, resistance training of a single lower limb muscle group in

83 hospitalized COPD patients was found to induce a statistically significant increase in

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84 quadriceps strength and to reduce the up-regulation of myostatin but did not result in altered
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85 levels of systemic inflammation or exercise capacity14. However, previous studies have

86 shown that resistance training improves exercise capacity in COPD outpatients when multiple
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87 muscles are trained18,21. We then speculate that whole-body resistance training (WBRT) is
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88 likely to be tolerated in symptomatic patients and can be used as a strategy to prevent muscle
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89 dysfunction during AE of COPD patients and, consequently, to improve exercise capacity and

90 HRQL without significant increases in the systemic inflammatory activity.

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92 The primary objective of this study was to evaluate the effects of a WBRT program on
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93 exercise capacity, HRQL, muscle strength and adverse events in patients hospitalized due to
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94 AE of COPD. The secondary objective was to investigate whether resistance training alters

95 systemic inflammatory activity and physical activity in daily life (PADL) during study.

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100 METHODS

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103 Patients

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104 This randomized and controlled clinical trial studied 46 COPD patients who had been

105 hospitalized due to disease exacerbation. Patients admitted in the ward were screened daily

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106 through the hospital database and if they were hospitalized due to COPD exacerbations

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107 according GOLD criteria1, patient was then contacted on the first day of hospitalization. The

108 inclusion criteria were the following: COPD (FEV1/FVC<70%) exacerbation characterized by

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109 an increase in sputum or cough or worsening of dyspnea1; no hospitalization in the last 30
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110 days; age between 40 and 85 years1,14; absence of musculoskeletal or neurological conditions

111 that might affect exercise performance; no participation in a rehabilitation program in the last
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112 6 months; and, absence of any other pulmonary diseases. The exclusion criteria were the
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113 following: patients transferred to the intensive care unit (ICU) before the 2nd day of
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114 hospitalization; patients exhibiting changes in mental status; worsening of hypoxemia

115 (PaO2<40 mmHg at room air) and/or respiratory acidosis (pH<7.25); hospitalization time less
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116 than 5 days; or inability to complete any of the evaluations. This study was a registered

117 clinical trial (clinicaltrials.gov identifier: NCT01786928). All patients were informed of the
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118 study and signed an informed consent form approved by the ethics committee of the São
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119 Paulo University Hospital.

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121 Experimental design

122 All patients were evaluated on 3 separate occasions: the 2nd day of hospitalization, at hospital

123 discharge and 1 month after hospital discharge. During each evaluation, the following

124 parameters were analyzed: six-minute walking distance (6MWD), muscle strength of upper
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125 and lower limbs, systemic inflammatory mediators, blood gas levels, lung function and

126 HRQL. PADL was also quantified during hospitalization and 1 month after. On the 2nd day

127 of hospitalization, patients performed baseline assessments and were then allocated into either

128 control (CG) or (TG) training groups. Evaluations were performed by a blinded evaluator.

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129 The randomization sequence was computer-generated by one investigator who was not

130 involved in the study, and allocation was concealed in sequentially numbered, sealed, and

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131 opaque envelopes.

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132

133 Control and whole-body resistance training protocols

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134 The CG received normal daily care, including chest physiotherapy to remove bronchial
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135 secretions, non-invasive ventilation if needed and verbal instructions to carry on with their

136 normal daily physical activities. Drug treatment and oxygen therapy were adjusted by the
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137 medical staff, according to the GOLD recommendations1. Patients did not receive any
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138 exercise program or recommendation to exercise after hospital discharge.

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140 The TG also received the same normal care as the CG, in addition to undergoing a WBRT
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141 program for the upper (shoulder flexion and abduction and elbow flexion) and lower (knee

142 extension and flexion and hip flexion) limbs by a physiotherapist in individualized sessions.
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143 The choice of muscles to be trained was based on data from previous literature21 and the
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144 results of a pilot study in our institution. Exercise training started on the 3rd day of

145 hospitalization, and every patient completed a minimum of 3 sessions during the study.

146 Exercise sessions were performed every morning with free weights in 2 sets of 8 repetitions22

147 in the sitting position. During exercises of shoulder abduction and flexion, a movement 90º to

148 the trunk, without full elevation of the limb, was performed. The initial load was set at 80% of

149 the load obtained in the 1-repetition maximum load test23 (maximum load exercise performed
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150 with dumbbells and anklets in the range of motion without any compensatory movements),

151 and adjustments in the load during subsequent sessions were made based on symptoms, Borg

152 dyspnea scores, and patient fatigue. Weight increases were conducted as tolerated by the

153 patient. Heart rate, oxygen saturation and modified Borg scale24 were recorded during

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154 exercise. Sessions would be interrupted when patients had any adverse event characterized by

155 Borg values ≥7 or exercise intolerance (heart rate <70% of predicted maximum, vertigo,

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156 syncope or cyanosis). Oxygen was administered and adjusted during exercise only in

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157 hypoxemic patients (saturation of peripheral oxygen (Sp02) <88%) with aim of maintaining

158 Sp02 between 92-94%.

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159
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160 Outcomes

161 Exercise capacity: was evaluated with the 6MWD test as previously described25. 6MWT was
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162 performed twice at each evaluation (2nd day of hospitalization, at hospital discharge and 1
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163 month after). Briefly, the patients were asked to walk as far as possible for 6 minutes in a
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164 corridor 30 meters long, no traffic and were verbally encouraged every minute. Rest breaks

165 were allowed when patients perceived intense dyspnea or discomfort. During the 6MWD test
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166 patients received supplemental oxygen (≤4 L/min) to maintain an oxygen saturation >88%.

167 Heart rate and oxygen saturation were monitored during test. Oxygen flow rate required to
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168 perform the initial 6MWD test was repeated in subsequent tests for each patient to avoid
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169 interference in the test performance.

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171 Health-related quality of life: was evaluated using the Saint George's Respiratory

172 Questionnaire, which is specific to COPD patients26 and has been validated in Portuguese27.

173 After a standardized instruction, patients fulfilled the questionnaire, always in the presence of

174 a single interviewer and doubts regarding issues were clarified according to the SGRQ
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175 manual. The questionnaire has 3 sections, namely symptoms, impact and activity, and the

176 total score ranges from 0 to 100, with a higher score corresponding to a worse quality of life

177 for each domain.

178

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179 Upper and lower limb muscle strength: maximal isometric voluntary strength was quantified

180 using a digital dynamometer in all three assessments. Signals were acquired and processed

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181 with software (EMGLab V1.1, EMG System, Brazila). The maximal isometric force was

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182 established by asking the patient to sustain maximal force for 5 seconds while receiving

183 standardized verbal encouragement28. The highest values from three tests, with a difference of

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184 <10%, were used in the analysis and one-minute rest was allowed between tests. Muscle
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185 strength was evaluated in the dominant upper (shoulder flexors and abductors and elbow

186 flexors) and lower (hip flexors and knee extensors and flexors) limbs for every muscular
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187 group. Patients were placed on a mobile examining chair. Wall-mounted traction bars were
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188 used to stabilize the pull straps attached to the strain gauge. For the tests of the muscle groups
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189 of the upper and lower limbs patients remained seated in a chair with knees and hips at 90°. A

190 strap was attached to the dominant side near the malleolus (lower limb) or hand (upper limbs)
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191 for evaluation of isometric contraction of the muscle group. For evaluation of the shoulder

192 flexors and abductors patients remained with the arm close to the trunk and extended elbow
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193 and made the respective contraction. For the elbow flexors, it was necessary that patients stay
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194 with elbow flexion of 90°. The examiner provided appropriate articular stabilizations to

195 obtain the maximal effort for each muscle function tested.

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197 Physical activity in daily life: was monitored using the monitor movement (Dynaport

198 Moviemonitor, McRoberts, Netherlandsb), which was developed and validated to evaluate

199 PADL in COPD patients29. Measurements were performed during a 12 hours period per day
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200 (from 8 a.m. to 8 p.m.) as previously described4 on the 3rd and 4th days of hospitalization, and

201 patients were instructed to maintain their regular PADL. One month after discharge PADL

202 was quantified at home over 2 days, excluding the weekend. The survey data were stored on a

203 memory card and were sent via internet to the manufacturer for evaluation. The analyzed

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204 PADL data are presented as the average time for each activity, assessed in the hospital and at

205 home.

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206

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207 Systemic inflammatory levels and blood gas analysis: Venous (for systemic inflammatory

208 mediators) and arterial (for blood gases analysis) blood samples were collected in the morning

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209 with patient´s breathing at ambient air. Venous samples were centrifuged at 1000 rpm, and the
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210 supernatant was stored at -70°C for later quantification of interleukin-6 (IL-6), IL-8, IL-10,

211 IL12p-70, IL-1β, tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP). CRP was
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212 measured using the nephelometry method, and systemic cytokines were assessed by bead kit

analysis (CBA, R&D Systems, USAc).

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215 Lung function: Spirometry (Microquark, Cosmed, USAd) was performed according to the
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216 criteria of the American Thoracic Society30, and values were expressed as percentages of

217 predicted values using the prediction equation for the Brazilian population31.
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218
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219 Statistical analysis

220 Quantitative variables were expressed as the mean and standard deviation, and categorical

221 variables were expressed as the total number of patients. Baseline values were compared

222 between groups using Student's t-test or Mann Whitney-U. Analysis of variance with repeated

223 measures was used to evaluate main effects for group vs. time interaction. Categorical

224 variables were compared using chi-square. The level of significance was set to 5% (p<0.05),
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225 and the statistical analysis was performed using the software package (SPSS 17, SPSS Inc,

226 USA). Sample size was calculated based on previous data from the literature14, to detect an

227 increase of 10.7±14.5% in quadriceps strength during AE of COPD between-group, using a

228 two-tailed independent t-test to yield 80% power and alpha ≤5%. Sample size was determined

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229 as 30 patients (15 per group) and a loss of 40% in the follow up was added.

230

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231 RESULTS

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232

233 Forty-six patients were randomized and 29 completed the study (Figure 1). Despite

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234 anticipating a patient attrition rate of 40%, it was necessary to randomize more 4 patients to
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235 obtain the calculated sample size. Characteristics of the groups are described in Table 1. At

236 baseline, there was no difference in the patient´s characteristics between the two groups. In
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237 addition, there was no difference between groups in lung function throughout the study. FEV1
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238 did not increase from day 2 until discharge from 39.1 ± 15.5% to 42.3 ± 14.4% (CG) and 41.7
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239 ± 13.6% to 44.6 ± 14.1% (TG) (p>0.05 inter and intra-group). Hospital stay in groups was 9.6

240 ± 3.2 (CG) and 8.0 ± 2.2 days (p>0.05). The TG performed an average of 5.6 sessions, and the
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241 TG experienced an average increase of 9.7% in the weight load. Adherence to resistive

242 training was 95%, and patients who refused complained of dyspnea, muscle soreness, and
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243 fatigue. Patients performed exercises with noninvasive ventilation in 35% of the sessions due
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244 to dyspnea (characterized by Borg scale ≥6). No patients exhibited any clinical deterioration

245 except oxygen desaturation (SpO2<88%) and increased dyspnea, which were reversed with

246 oxygen or increasing supplemental oxygen. Training session lasted 90 minutes, on average.

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248 At baseline, the patients from the TG and CG showed similar strength in the hip flexors

249 (11.6±4.5 kg and 13.0±5.1 kg, respectively) and knee flexors (13.0±5.5 kg and 15.6±4.8 kg;
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250 p>0.05), but at discharge from the hospital, only the TG showed an increase in the hip flexors

251 and knee flexors (17.1±5.4% and 16.2±4.7%, respectively; p<0.05; Figure 2A-F). Patients in

252 the CG exhibited a decrease in knee extensors and hip flexors strength and a return to baseline

253 values in the hip flexors after 30 days (Figures 2D and 2E). During hospitalization, the

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254 patients from the TG exhibited in the 6MWD an increase in of 160(±61) m, compared with

255 the CG, which showed an increase of 11(±83) m (74.2±30.7% vs. 4.1±5.1%, respectively;

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256 p<0.05; Figure 3). In addition, there were no differences between the groups in oxygen supply

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257 during the 6MWD.

258

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259 The patients in the TG and CG did not demonstrate significant differences in HRQL at
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260 hospital discharge, when compared with HRQL on the 2nd day of hospitalization. The TG

261 exhibited a significant improvement (negative value) in the impact domain after 1 month
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262 compared with the CG (p<0.05; Table 2). Both groups demonstrated similar improvements in
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263 the activity domain 1 month after compared with values obtained at hospitalization (time
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264 interaction), with no significant differences between the groups (group interaction) (p>0.05).

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266 Patients in the TG and CG remained mostly inactive (sitting + lying) during hospitalization

267 and the first month post-discharge (87 and 70%, respectively; no significant difference
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268 between groups). Despite this inactivity, both groups significantly improved their active time
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269 (standing + walking) by approximately 30% 1 month after (p<0.05), and no difference was

270 observed between the two groups.

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272 The TG exhibited a reduction in the levels of TNF-α, IL-6 and IL-8 1 month after

273 hospitalization compared with changes observed during hospitalization (p<0.05;time

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274 interaction; Table 3). No difference was observed in the other inflammatory mediators

275 between the two groups during the hospitalization period or 1 month post-discharge.

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277 DISCUSSION

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278

279

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280 This randomized controlled study demonstrated that WBRT increases muscle strength in most

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281 trained muscles and improves exercise capacity and HRQL without changes in the levels of

282 systemic inflammation in COPD patients during disease exacerbation. Despite these benefits,

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283 no change was observed in the PADL during or after hospitalization.
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285 Deleterious effects of hospitalization in COPD patients have been previously described and
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286 include reductions in muscle strength4, health status3 and PADL4. Our study clearly shows
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287 that WBRT can be a useful intervention to reduce and/or prevent decreases in muscle strength
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288 during hospitalization, as the average increase in the strength of most muscles was 1.5% per

289 day. This increase was even higher if we also consider the average decrease of 10% during the
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290 8 days of hospitalization observed in the CG, which are similar to previous reports of a 1%

291 per day decline in muscle strength of the lower limbs in hospitalized COPD4 and non-COPD
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292 patients32. We believe that an average improvement of 12% in most exercised muscles is
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293 clinically relevant because similar improvements were shown after 6 months in a pulmonary

294 rehabilitation program in stable COPD patients33. It can be speculated that the increase in

295 muscle function observed during a short training period, as in our study (5.6 sessions), may be

296 due to an improvement in neuromuscular coupling (neurological adaptation)34. In addition,

297 this type of training reversed the catabolic effects of hospitalization by reducing myostatin
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298 expression and also might have exerted an increase markers of satellite cell

299 upregulation/activation (myogenin and MyoD)14.

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301 6MWT was chosen because has been considered an easy and reliable method to assess

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302 exercise capacity and also previously used in hospitalized COPD patients 14,15. Our results

303 show an improvement in the 6MWD that remained even 1 month after discharge. Previous

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304 study from Troosters et al14 did not show any improvement in the exercise capacity. A

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305 possible explanation to justify at least partially the difference between both studies could be

306 the fact that we trained a greater number of muscles, and most of the trained muscles showed

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307 significant strength improvement at hospital discharge, although the knee extensor strength
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308 improved by only 7.2% (Figure 2D). These improvements in muscle strength could have

309 directly influenced the observed increase in the 6MWD because these muscles are used for
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310 walking. Interestingly, our results are similar to previous studies of COPD outpatients
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311 participating in upper and lower limb resistance training showed an improvement in the

exercise capacity18,21. These results also seem clinically relevant because walking distance has
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313 been implicated in predicting the risk of COPD exacerbation and is strongly associated with
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314 HRQL6. In addition, the average increase (169.6 meters) in the 6MWD was greater than the

315 54 m described as the minimum distance necessary to detect a clinical effect35. It is possible
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316 to affirm that improvements in impact domain of HRQL resulted from the confidence gained
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317 by patients who exhibited improved muscle strength and exercise capacity.

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319 In a systematic review, O’Shea and coworkers17 suggested that short-term progressive

320 resistance training increased muscle strength in stable COPD patients and may improve

321 elements of performance of daily activities; however, this effect was not observed in our

322 study. This lack of improvement in PADL may have occurred because either requires a longer
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323 period of exercise training to induce a more active lifestyle or because COPD patients may be

324 reluctant to increase daily physical activity fearing to re-exacerbate. The requirement of a

325 training program with a greater number of sessions to induce higher levels of PADL has been

326 previously described by Pitta and coworkers36.

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328 During hospitalization, the CG experienced a significant loss in the strength of some muscles

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329 in the lower limbs but not in the upper limbs, and we hypothesize that this occurred because

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330 the upper limb muscle groups are not anti-gravitational and, therefore, are less prone to the

331 effects of immobility. In accordance with this hypothesis, bed rest in healthy volunteers

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332 reduced the diameter of the vastus lateralis and gastrocnemius without modification of the
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333 biceps37. Therefore, it is possible that resistance training of the lower limbs could be used to

334 attenuate the effects of immobility.

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336 Based on our results, we add information in the literature and minimize the idea that WBRT
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337 performed during exacerbation could worsen clinical and inflammatory status of COPD

338 patients since no increase in systemic inflammation, corticosteroid use or length of hospital
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339 stay was observed in the patients who received to this intervention. This concern is based on

340 previous studies suggesting that a unique series of exercises causes an abrupt increase in the
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341 levels of inflammatory cytokines38,39. However, contrary to these results, resistance training
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342 does not increase the levels of inflammatory markers or cause clinical deterioration14. In our

343 study, we observed a significant decrease in inflammatory markers throughout the study in the

344 TG but not in the CG. However, we are not entirely convinced that this reduction in

345 inflammatory markers was due entirely to the resistance training, but it might have been due

346 to a larger number of patients in the TG having stopped smoking compared to the CG (4 vs. 1,

347 respectively).
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348 Study Limitations

349 This study has clear limitations. First, the tests used to measure muscle strength in this study

350 are dependent on patient motivation. However, we tried to minimize this effect by only

351 considering the three tests with the greatest values, with a maximum difference among tests of

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352 10%, and to determine the muscle strength based on testing of the greater value. Second, the

353 results obtained by resistance training were only possible in patients admitted to a ward; we

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354 believe that more severely ill patients admitted to an ICU would barely be able to complete

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355 these assessments at the beginning of the study or conduct training at this intensity. Since the

356 sample size was calculated based on muscle strength, it is possible that the non-statistical

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357 differences observed in two CRQ domains and PADL may lead to type II error in these
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358 outcomes. Third, the small number of patients may lead to type II error, however, we reached

359 the sample size previously calculated. Moreover, the number of patients included in our study
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360 is similar to those studied by Troosters and colleagues14. Fourth, in our study, we had a 37%
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361 loss to follow up that can be considered large and probably reflects the patient´s severity,
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362 since 35% of patients were referred to ICU. Another reason for the loss during follow-up was

363 because there was a high rate of early discharge and our hospital ethical committee did not
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364 allow us to keep patients for a minimal amount of time, as it has been done in previous

365 studies4,14. In addition, there was a greater loss to follow up in the CG due to the fact that two
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366 patients died for reasons unrelated to COPD (rupture of aortic aneurysm and sepsis of
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367 abdominal origin) and two patients refused to attend the hospital 1 month after. To better

368 understand the differences between groups we conducted a secondary analysis (data not

369 shown) with baseline characteristics of patients who had dropped out, and there was no

370 statistical difference between groups. However, to strengthen our results, we conducted a

371 secondary data analysis using the last value carried forward imputation technique and we still

372 observed a similar improvement in the 6MWT and most studied muscles in TG (data not
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373 shown). The only exception was observed in the knee extensors and hip flexors muscles that

374 did not show difference intra-group (CG), but this occurred because the imputation data

375 analysis in the control group reduced the loss in muscle strength observed in the hospital

376 discharge. Finally, the prolonged duration in some resistance sessions (about 90 minutes)

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377 hinders the implementation of this protocol in the daily routine of care; however, training

378 could be done only in a reduced number of muscles (those most affected) which would reduce

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379 the session duration.

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380

381 CONCLUSIONS

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384 Our results suggest that WBRT improves lower and upper limb muscle strength and exercise
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385 capacity, without increasing harmful systemic inflammation. However, it did not change
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386 PADL in the hospital or at home. In addition, our results also suggest that the WBRT proved
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387 to be safe and feasible to implement in exacerbated COPD patients admitted to a medical

388 ward.
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398

399 REFERENCES

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401

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402 1. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and

403 prevention of chronic obstructive pulmonary disease – GOLD Executive summary. Am J

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404 Respir Crit Care Med. 2007;176(6):532–555.

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422 9. Bernard S, LeBlanc P, Whittom F, et al. Peripheral muscle weakness in patients with

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441 16. Akima H , Kubo K, Imai M, et al. Inactivity and muscle: effect of resistance training

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469 no Brasil. J Pneumol. 2000;26(3):119-125.

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470 28. McNair PJ, Depledge J, Brettkelly M, Stanley SN. Verbal encouragement: effects on

471 maximum effort voluntary muscle action. Br J Sports Med. 1996;30(3):243-245.

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476 31. Pereira CAC, Barreto SP, Simões JG, et al. Reference values for spirometry for the

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478 32. Suesada MM, Martins MA, Carvalho CR. Effect of short-term hospitalization on

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481 33. Troosters T, Gosselink R, Decramer M. Short- and long-term effects of outpatient
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482 rehabilitation in patients with chronic obstructive pulmonary disease: a randomized trial. Am J
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483 Med. 2000;109(3):207–212.

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484 34. Gabriel DA, Kamen G, Frost G. Neural adaptations to resistive exercise: mechanisms and

485 recommendations for training practices. Sports Med. 2006;36(2):133-149.

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486 35. Holland AE, Hill CJ, Rasekaba T, Lee A, Naughton MT, McDonald CF. Updating the

487 minimal important difference for six-minute walk distance in patients with chronic
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488 obstructive pulmonary disease. Arch Phys Med Rehabil. 2010;91(2):221-225.

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489 36. Pitta F, TroostersT, Probst VS, Langer D, Decramer M, Gosselink R. Are patients with

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491 37. Boer MD, Seynnes OR, Pinot R, Mekjavit IB, Biolo G, Narici MV. Effect of 5 weeks

492 horizontal bed rest on human muscle thickness and architecture of weight bearing and non-

493 weight bearing muscles. Eur J Appl Physiol. 2008;104(2):401–407.

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494 38. Febbraio MA, Pedersen BK. Muscle-derived interleukin-6: mechanisms for activation and

495 possible biological roles. FASEB J. 2002;16(11):1335–1347.

496 39. Rabinovich RA, Figueras M, Ardite E, et al. Increased tumour necrosis factor-α plasma

497 levels during moderate-intensity exercise in COPD patients. Eur Respir J. 2003;21(5):789-

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498 794.

499 40. Enright PL and Sherril DL. Reference equations for the six-minute walk in healthy adults.

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500 Am J Respir Crit Care Med. 1998;158(5 Pt 1):1384–1387.

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501

502 SUPPLIERS

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503
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504 a. EMG SYSTEM DO BRASIL LTDA, Rua Porto Principe, 50 - Vila Rubi CEP 12245-572 -

505 São José dos Campos – SP

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506 b. Mcroberts, Raamweg 43 2596 HN The Hague The Netherlands

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507 c. R&D Systems, Inc. 614 McKinley Place NE Minneapolis, MN 55413.

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508 d. Cosmed, 1850 Bates Ave, Concord, CA 94520.

509
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510

511 FIGURE LEGENDS

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512
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513 Figure 1: Flowchart of randomized patients

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515 Figure 2: Values are presented as the mean±SEM in the training group (solid circles) and the

516 control group (open circles) for the shoulder abductors (A), elbow flexors (B), elbow flexors

517 (C), knee extensors (D), hip flexors (E) and knee flexors (F). The values presented in the y-
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518 axis of Figures A-F are expressed as percent of the values obtained on Day 2. The unit of

519 measurement of the assessment of peripheral muscle strength was in Kg.

520 *p<0.05 indicates a significant difference between the training and control groups.
†
521 p<0.05 indicates a significant difference within group compared to day 2.

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§
522 p<0.05 indicates a significant difference within group compared discharge.

523

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524 Figure 3: Values are presented as the mean±SEM in the training group (solid circles) and

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525 control group (open circles) for the six-minute walking distance. The values presented in the

526 y-axis are expressed as percent of the values obtained on Day 2. The unit of measurement of

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527 6-minute walk test was in meters.
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528 *p<0.05 indicates a significant difference between the training and control groups.
†
529 p<0.05 indicates a significant difference within group compared to day 2.
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Table 1 – Baseline characteristics of the studied patients

Outcomes Control Group (n=14) Training Group (n=15)

Age (years) 67.8 ± 9.0 64.1 ± 12.5

Gender (F/M) 4/10 7/8

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Current smokers 5 9

Smoking (pack-years) 50.8 ± 20.4 48.7 ± 19.3

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Number of hospitalizations in past year 5 9

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Blood gas

PaO2 (mmHg) 51.5 ± 10.6 45.8 ± 10.6

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PaCO2 (mmHg) 51.7 ± 17.2 49.8 ± 17.9
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BODE index (0-10) 6.1 ± 2.2 6.9 ± 1.7

Body mass index (Kg/m2) 23.4 ± 4.6 22.3 ± 5.1

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FEV1 (% predicted) 39.1 ± 15.5 41.7 ± 13.6

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6MWD (meters) 283.7 ± 129.1 228.7 ± 98.5

6MWD (% predicted)*
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46.6 ± 19.7 37.4 ± 15.8

MMRC (0-4) 3.5 ± 0.7 3.8 ± 0.5

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SGRQ (0-100)

Symptom 69.2 ± 20.9 71.0 ± 16.5

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Activity 83.3 ± 18.5 89.6 ± 15.2

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Impact 50.7 ± 21.0 60.0 ± 18.3

Total 63.5 ± 18.6 71.6 ±15.3

Quadriceps strength (Kg) 29.8 ± 11.7 26.3 ± 9.5

Hospital staying (days) 9.6 ± 3.2 8.0 ± 2.2

Noninvasive ventilation 8 9
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Legend: Values are presented as mean ± standard deviation, except for gender, current

smokers, patients who were hospitalized in the last year and noninvasive ventilation that

are described as number of patients; M= male; F = female; PaCO2 = pressure arterial of

carbon dioxide; PaO2 = pressure arterial of oxygen; FEV1 = forced expiratory volume in

the first second; 6MWD = 6-minute walking distance; MMRC= modified Medical Research

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Council dyspnea scale; SRGQ=Saint George Respiratory Questionnaire. Number of

hospitalizations in past year was specifically due to exacerbation of COPD. Blood gas was

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collected in ambient air. Noninvasive ventilation refers to the number of patients using

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noninvasive ventilation by medical prescription. Quadriceps strength shown in table was

obtained using a digital dynamometer. *Reference values for the predicted 6MWD were

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extracted from reference 40. Values were compared between groups using the Student’s t-
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test or Mann Whitney-U. No statistical difference was observed between both groups.
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Table 2 – Percentage changes in health-related quality of life during hospitalization and 1

month after hospital discharge

Control Group Training Group

at hospital at hospital

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1 month after 1 month after
Domains†
discharge discharge

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-4.8 ± 5.9 -4.1 ± 14.7 1.1 ± 15.7 -3.3 ± 22.2
Symptom
-10.1 ± 19.4 -29.1 ± 23.6* -14.3 ± 13.7 -28.7 ± 26.6*
Activity

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-3.1 ± 37.4 -14.6 ± 46.6 -13.3 ± 18.9 -30.6 ± 25.7* #
Impact
-2.4 ± 19.6 -18.8 ± 28.1* -10. 7 ± 11.8 -24.3 ± 21.5*

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Total
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Legend: Values are presented as mean ± standard deviation. †The values presented for each

CRQ domain (symptom, activity and impact) refers to the mean difference obtained between
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either at hospital discharge or after 1 month of hospitalization minus and the values obtained

on 2nd day of hospitalization. Negative values represent improvement in health related quality
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of life in relationship to baseline values. ANOVA 2-way was used to evaluate main effects for
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group, time and interaction. *p<0.05 compared with intragroup 1 month after. p<0.05

compared with intergroup 1 month after.

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Table 3 – Changes in serum levels of systemic inflammation during hospitalization and 1

month after hospital discharge

Control Group Training Group

Outcomes At hospital At hospital

1 month after 1 month after

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(pg/ml) † discharge discharge

CRP -14.2 ± 24.1 -23.5 ± 33.6 -42.0 ± 49.1 -44.9 ± 53.0

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IL12p-70 -0.2 ± 1.8 -0.2 ± 1.6 -0.7 ± 0.8 -0.6 ± 1.0

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TNF-α -0.9 ± 4.8 -1.0 ± 4.4 -2.6 ± 4.5 -3.8 ± 5.4*

IL-10 1.2 ± 4.1 -1.0 ± 2.6 0.7 ± 4.7 0.9 ± 5.4

IL-6 -1.3 ± 3.0

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-1.8 ± 3.4 -1.8 ± 6.0 -3.6 ± 6.5*
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IL-1β -0.5 ± 3.54 -0.5 ± 3.3 -1.3 ± 1.7 -2.8 ± 5.3

IL8 -6.6 ± 11.6 -8.6 ± 14.3 -7.1 ± 5.1 -9.7 ± 7.9*

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Legend: Values are presented as mean ± standard deviation. †The values presented for
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each outcome refers to the mean difference obtained between either at hospital discharge
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or after 1 month of hospitalization and the values obtained on 2nd day of hospitalization.

Negative values represent a reduction in the mean values of the outcome in relationship to
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baseline values. CRP=C-reactive protein; IL=interleukin; TNF-α= tumor necrosis factor-α.

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ANOVA 2-way was used to evaluate main effects for group, time and interaction*p<0.05
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compared with intragroup 1 month after hospital discharge.

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