Journal of Clinical Medicine Review Data Reproducibility and Effectiveness of Bronchodilators for Improving Physical Activity in COPD Patients Yoshiaki Minakata * and Seigo Sasaki Department of Respiratory Medicine, National Hospital Organization Wakayama Hospital, Wakayama 644-0044, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-738-22-3256 Received: 7 September 2020; Accepted: 27 October 2020; Published: 29 October 2020 Abstract: Increasing physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD) is an important issue, however, the effect of bronchodilators on PA is still controversial. The indicators of PA, as measured by an accelerometer, can easily fluctuate based on several factors, which might cause inconsistent results. In this review, we listed the indicators of PA and the factors influencing the reproducibility of indicators of PA, and reviewed reports in which the effects of bronchodilators on PA were evaluated by an accelerometer. Then, we investigated the association between the processing of influencing factors and the effectiveness of bronchodilators for improving the PA of COPD patients. Fifteen reports were extracted using the PubMed database. In all seven reports in which adjustment was performed for at least two of four influencing factors (non-wear time, data from days with special behavior, environmental factors, and number of valid days required to obtain reproducible data), bronchodilators showed beneficial effects on PA. No adjustment was made for any of these factors in any of the four bronchodilator-ineffective reports. This suggests that the processing of influencing factors to secure reproducibility might affect the results regarding the effectiveness of bronchodilators for improving PA in COPD patients. Keywords: physical activity; pharmacological treatment; COPD; reproducibility; sedentary behavior 1. Introduction Chronic obstructive pulmonary disease (COPD) is a disease characterized by airflow limitation and air trapping, which is usually caused by exposure to noxious particles or gases [1]. Air trapping leads to the sequential development of exertional dyspnea and decreased exercise capacity. Physical activity (PA) is reduced by decreased exercise capacity and other factors, such as psychological, socio-economic, comorbidities, and/or skeletal muscle weakness (Figure1). This leads to a downward spiral of inactivity which predisposes patients to a reduced quality of life, and increased rates of hospitalization and mortality [2–6]. Reduced level of PA in COPD was associated with exacerbation [6–10], FEV1 decline [11–15], and mortality [4–6]. Furthermore, PA level was reported to be the strongest risk factor for all-cause mortality in COPD patients [5]. Therefore, the maintenance or improvement of PA becomes an important target for the management of COPD patients [1]. Recently, objective measurements using an accelerometer have been widely used to evaluate PA rather than questionnaires, which were mainly used but tended to overestimate the PA [16,17]. An accelerometer can detect acceleration in one, two, or three dimensions (uniaxial-, biaxial-, triaxial-accelerometer, respectively) and can calculate the values of several indicators of PA. J. Clin. Med. 2020, 9, 3497; doi:10.3390/jcm9113497 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, 3497 2 of 23 J. Clin. Med. 2020, 9, x 2 of 23 Figure 1. The downward spiral of inactivity in COPD. Physiological changes lead to dyspnea and decreased exercise capacity.capacity. Physical activity is reduced by decreased exercise capacity and other factors, such as psychological, socio-economic,socio-economic, comorbidities,comorbidities, andand/or/or skeletalskeletal musclemuscle weakness.weakness. ‘Physical‘Physical activity activity’’ can be defineddefined as “any bodily movement produced by skeletal muscles that results in energyenergy expenditure” [[18]18],, but it is usuallyusually defineddefined as physicallyphysically active behavior that is comparable to moderate to vigorous vigorous-intensity-intensity PA (MVPA) [[19,2019,20].]. ‘Physical‘Physical inactivity’inactivity’ is defineddefined as “a“a PAPA levellevel thatthat is not susufficientfficient for meeting present PA recommendations” [[20,2120,21].]. Physical inactivity in adults isis oftenoften defineddefined using using threshold threshold activity activity values: values: the the non-achievement non-achievement of 150of 150 min min of MVPAof MVPA per weekper week or 75 or min 75of min vigorous-intensity of vigorous-intensity PA (VPA) PA per(VPA) week per or week an equivalent or an equivalent combination combination of moderate- of andmoderate vigorous-intensity- and vigorous activity-intensity [20 activity]. In contrast, [20]. In ‘sedentarycontrast, ‘sedentary behavior’ behavior is defined’ is asdefined “any wakingas “any behavior characterized by an energy expenditure 1.5 metabolic equivalents (METs), while in a sitting, waking behavior characterized by an energy expenditure≤ ≤1.5 metabolic equivalents (METs), while recliningin a sitting, or reclining lying posture” or lying [20 posture”,22,23] (Table [20,22,231). ] (Table 1). Table 1. Definitions of physical activity. Table 1. Definitions of physical activity. TermsTerms Definitions Definitions (Originally(Originally)) Any Any bodily bodily movement movement produced produced by by skeletal skeletal muscles muscles that that results results in in Physical activity energyenergy expenditure expenditure [18] [18 ] Physical (Practically) Physically active behavior that is comparable to MVPA [19,20] activity A( PAPractically level that) Physically is not suffi activecient forbehavior meeting that the is present comparable PA recommendations to MVPA [19,20] [20,21] Threshold: [20] A PA level that is not sufficient for meeting the present PA recommendations Physical inactivity The non-achievement of 150 min of MVPA per week or [20,21] 75 min of VPA per week or Physical an equivalent combinationThreshold of moderate-: [20] and vigorous-intensity activity inactivity Any wakingThe behavior non-achievement characterized of by150 an min energy of MVPA expenditure per week1.5 orMETs, while in a Sedentary behavior ≤ sitting,75 reclining min of VPA or lying per week posture or [20,22,23] an equivalent combination of moderate- and vigorous-intensity activity MVPA, moderate to vigorous-intensity physical activity; VPA, vigorous-intensity physical activity; METs, metabolicSedentary equivalents. Any waking behavior characterized by an energy expenditure ≤1.5 METs, while in behavior a sitting, reclining or lying posture [20,22,23] BronchodilatorsMVPA, moderate to are vigorous key drugs-intensity in pharmacotherapy physical activity; VPA, for COPD vigorous and-intensity have been physical reported activity; to have beneficialMETs, e metabolicffects on theequivalents pulmonary. function, dyspnea, exercise capacity, and exacerbations in COPD patients [24–38]. However, its effectiveness in improving PA has differed among reports and is still controversial.Bronchodilators The PA are in key COPD drugs patients in pharmacotherapy can be influenced for COPD by many and factors; have been thus, reported it might to not have be improvedbeneficial effects by pharmacotherapy on the pulmonary alone. function, On the dyspnea, other hand, exercise the capacity, values of and indicators exacerbations of PA can in COPD easily fluctuatepatients [24 based–38].on However, several factors,its effectiveness in other in words, improving the indicators PA has differed of PA show among poor reports reproducibility. and is still Thiscontroversial. might be theThe reasonPA in whyCOPD the patients different can studies be influenced have reported by many inconsistent factors; thus, results it regardingmight not thebe eimprovedffects of bronchodilators by pharmacotherapy on PA inalone. COPD On patients the other [31 hand,,39–52 the]. values of indicators of PA can easily fluctuate based on several factors, in other words, the indicators of PA show poor reproducibility. This might be the reason why the different studies have reported inconsistent results regarding the effects of bronchodilators on PA in COPD patients [31,39–52]. J. Clin. Med. 2020, 9, 3497 3 of 23 J. Clin. Med. 2020, 9, x 3 of 23 InIn thisthis review,review, we we listed listed the the indicators indicators of of PA PA and and the the factors factors influencing influencing the the reproducibility reproducibility of of indicatorsindicators ofof PA,PA, and and reviewed reviewed reports reports that that evaluated evaluated thethe eeffectsffectsof ofbronchodilators bronchodilators onon PAPA in in COPD COPD patientspatients using using an an accelerometer. accelerometer. Then, Then, we we investigated investigated the the influence influence of of these these factors factors on on the the resultsresults of of thethe e effectivenessffectiveness of of bronchodilator bronchodilator treatment. treatment. Finally,Finally,we we described describedthe the sedentary sedentarybehavior behaviorthat thathas has receivedreceived attention attention as as a a risk risk factor factor for for mortality mortality independent independent of of PA. PA. 2.2. IndicatorsIndicators ofof PAPA SeveralSeveral indicatorsindicators havehave beenbeen usedused toto evaluateevaluate PAPA with with an an accelerometer. accelerometer. AccelerometersAccelerometers areare roughlyroughly divided divided into into two two types: types: one one is is a a devicedevice that that detectsdetects the the duration