Global muscle dysfunction as a risk factor of readmission to hospital due to COPD exacerbations

Global muscle dysfunction as a risk factor of readmission to hospital due to COPD exacerbations
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  Global muscle dysfunction as a risk factor of readmission to hospital due to COPD exacerbations Jordi Vilaro´ a,g , Alba Ramirez-Sarmiento b,g ,Juana M a Martı´nez-Llorens b , Teresa Mendoza c , Miguel Alvarez d ,Natalia Sa´nchez-Cayado e , A´ngeles Vega e , Elena Gimeno f  , Carlos Coronell b ,Joaquim Gea b , Josep Roca f  , Mauricio Orozco-Levi b, * a FCS Blanquerna, Universitat Ramon Llull, Barcelona, Spain b Grupo de Investigacio´n en Lesio´n, Respuesta Inmune y Funcio´n Pulmonar (LIF), Instituto Municipal de Investigacio´n Me´dica(IMIM), Servei de Pneumologia, Hospital del Mar; CIBER of Respiratory Diseases (CIBERES), ISCIII, Barcelona, Spain c Servicio de Rehabilitacio´n Hospital Insular, Las Palmas de Gran Canaria, Spain d Hospital General de la Defensa, Madrid, Spain e Instituto Nacional de Silicosis, Oviedo, Spain f Servei de Pneumologia i Al.lergia Respirato`ria (CIBERESP), Hospital Clı´nic i Provincial, Barcelona, Spain Received 2 February 2010; accepted 3 May 2010Available online 11 June 2010 KEYWORDS Respiratory andperipheral muscles;Muscle weakness;Nutrition;Exacerbation;Hospitalisation Summary Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with severalmodifiable (sedentary life-style, smoking, malnutrition, hypoxemia) and non-modifiable(age, co-morbidities, severity of pulmonary function, respiratory infections) risk factors. Wehypothesise that most of these risk factors may have a converging and deleterious effectson both respiratory and peripheral muscle function in COPD patients. Methods:  Amulticentrestudywascarriedoutin121COPDpatients(92%males,63  11yr,FEV 1 ,49  17%pred). Assessments included anthropometrics, lung function, body composition usingbioelectricalimpedanceanalysis(BIA),andglobalmusclefunction(peripheralmuscle(dominantand non-dominant hand grip strength, HGS), inspiratory (PI max ), and expiratory (PE max ) musclestrength). GOLD stage, clinical status (stable vs. non-stable) and both current and past hospitaladmissions due to COPD exacerbations were included as covariates in the analyses. Results:  Respiratory and peripheral muscle weakness were observed in all subsets of patients.Muscle weakness, was significantly associated with both current and past hospitalisations.Patients with history of multiple admissions showed increased global muscle weakness after  * Corresponding author at: Servei de Pneumologia, Hospital del Mar, Passeig Marı´tim 25-29, E-08003 Barcelona, Spain. Tel.:  þ 34932483138; fax:  þ 34 932213237. E-mail address: (M. Orozco-Levi). g For authorship purposes, J. Vilaro and A. Ramirez-Sarmiento contributed equally to this project and share the rank of first author. available at www.sciencedirect.comjournal homepage: Respiratory Medicine (2010)  104 , 1896 e 19020954-6111/$ - see front matter   ª  2010 Elsevier Ltd. All rights reserved.doi:10.1016/j.rmed.2010.05.001  adjusting by FEV 1  (PE max , OR Z 6.8,  p < 0.01; PI max , OR Z 2.9,  p < 0.05; HGSd, OR Z 2.4, andHGSnd, OR Z 2.6,  p Z 0.05). Moreover, a significant increase in both respiratory and peripheralmuscle weakness, after adjusting by FEV 1 , was associated with current acute exacerbations. Conclusions:  Muscledysfunction,adjustedbyGOLDstage,isassociatedwithanincreasedriskofhospitaladmissionsduetoacuteepisodesofexacerbationofthedisease.Currentexacerbationsfurther deteriorate muscle dysfunction ª 2010 Elsevier Ltd. All rights reserved. Introduction Chronic obstructive pulmonary disease (COPD) is a relevanthealth problem in most developed countries due to its highprevalence and enormous costs, both direct and indirect,which generate a tremendous burden on healthcaresystems. 1 In Spain, COPD affects about 9% of the adultpopulation (40 e 70 years old) and is the fourth largest causeof hospital admission and death in this age group. 1,2 The natural history of COPD implies a series of respira-tory symptoms and periods of clinical exacerbation thatdecrease not only the quality of life but also life expec-tancy. 3 Exacerbation is clinically defined by worseneddyspnoea, worsened sputum volume and/or change in itscolour, and new or worsened cough. 2 There is limitedinformation describing the clinical e physiological changesin patients admitted to hospital with an exacerbation ofCOPD. Although several groups of authors have studied therisk factors of exacerbation in relation to hospital read-mission for COPD patients, no study has specifically focusedon muscle dysfunction.One of the frequent extrapulmonary manifestations ofCOPD is skeletal muscle dysfunction and wasting. 4 Withincreasing severity of disease, patients with COPD loosemuscle bulk, especially in their thighs and upper arms. Over time, exercise endurance decreases in these patients andthey complain of dyspnoea and leg discomfort with mild tomoderate workload increases. 5 These symptoms curtailexercise capacity and compromise cardiac fitness, whichfurther limits exercise tolerance, creating a vicious down-ward spiral that can eventually lead to generalised debilityand immobility. 6 Skeletal muscle dysfunction contributes toreduce health status of patients with COPD and substan-tially increases the risk of mortality, independent oftraditional markers of COPD mortality such as baseline lungfunction, age, and cigarette smoking. 7,8 Encouragingly,early interventions with exercise programmes may restoresome of the lost health status related to muscle dysfunctionand increase patients’ exercise tolerance and stamina. 9 It is clearly recognised that, whereas one group of COPDpatients may rarely need hospital admission during exac-erbations, other groups of patients are prone to multipleadmissions. 2 There are a few of studies suggesting thatinspiratory and expiratory muscle dysfunction could act asa modifiable risk factor of hospital admission in patientswith COPD. Martı´nez-Llorens et al. 10 using a case-controlstudy design showed that exacerbations of COPD associateswith pronounced deleterious changes in skeletal musclefunction in association with acute loss of muscle mass. Inother setting, Gonza´lez et al. 11 clearly identified thatrespiratory muscle overload (defined as a high pressure-time index of the inspiratory muscles) as a risk factor ofhospital readmission in a 1-year follow-up of a cohort ofpatients with moderate-to-severe COPD. We hypothesisedthat patients with higher risk for severe exacerbations havea limited ventilatory reserve and that respiratory muscledysfunction underlies and negatively affects the balancebetween functional reserve and acute loading imposed byexacerbation. 12 We thus considered that (1) a greater respiratory muscle dysfunction can be present even at thestable clinical conditions in patients with greater risk for hospital admission, and (2) that global muscle involvementcould be captured by measuring inspiratory, expiratory andperipheral muscle strength. To test these hypotheses,a multicentre study was performed in two subsets of COPDpatients defined by their clinical stability (present or absent). In a post-hoc analysis, the history of hospitaladmissions (none, current, or multiple hospitalisations) wastaken in account in the analyses. Methods This was a multicentre, cross-sectional study carried outover two consecutive years. The principles of the Declara-tion of Helsinki 13 were applied and all patients gave writteninformed consent to participate. The study was approvedby the Ethics Committees at all the centres participating inthe study.Candidates were all patients with COPD assigned to twocohorts: 1) patients admitted to the hospital due to exac-erbations of COPD, and 2) stable COPD patients thatcurrently go to the hospital for their regular follow-up.Those subsets of patients were defined by their clinicalstability (present or absent). In a post-hoc analysis, thehistory of hospital admissions (none, current, or multiplehospitalisations) was taken into account for the definitionof study groups.  Group 1  was composed of patients whoattended regular hospital follow-up but had never requiredhospital admission.  Group 2  included clinically stable COPDpatients defined as three or more months from the lastexacerbation with a history of multiple (three or more)hospital admissions during the last year.  Group 3  wascomposed of patients admitted to hospital for the very firsttime with a physician diagnosis of an acute exacerbation ofCOPD. Finally,  Group 4  included patients with acuteexacerbation but admitted to the hospital on multiple(three or more) occasions. Only patients requiring level IIadmission that is hospitalisation in a medical ward but notin the ICU 14 were included in the study. In the latter twogroups (3 and 4), a respiratory physiotherapist performedan early ( < 48 hours of admission) assessment that included:1) body weight; 2) inspiratory and expiratory musclestrength (expressed as maximal expiratory and inspiratorymouth pressures, respectively); 3) peripheral muscleMuscle dysfunction and risk of exacerbation in COPD 1897  strength (measured by hand dynamometry) and 4) bodycomposition (bioelectrical impedance analysis, expressedin both absolute and relative values). Conventional bloodand biochemical analyses were also taken for all patientsand all prescribed drugs were systematically recorded.Exclusion criteria were as follows: pneumonia, infectionfrom any other organ, left heart failure, previous myocar-dial infarction, previous or present pulmonary embolism,asthma or the need for ventilatory support. In addition,patients were excluded if they had chronic respiratoryfailure and relevant comorbidity. These were defined as thepresence or suspicion of recent orthopaedic, medical, or surgical diseases that could affect muscle structure andfunction and introduce confusion factors into the analysis.Peripheral oedema, suspicion of ascites, hormonal therapyfor causes other than hyperglycaemia associated withsteroid therapy during admission, and history of chronicsystemic steroid therapy were considered additionalexclusion criteria Current smoking was not considered anexclusion criterion. Measurements Body weight (in kilograms) was assessed using officiallyapproved floor scales (SECA, Berlin, Germany). Patientswere weighed in light clothing, barefoot and with an emptybladder. Values were rounded to nearest 100 g. Height (inm) was measured using a wall-mounted stadiometer. Bodymass index (BMI) was calculated with the formula weight/height 2 (kg/m 2 ). To assess body compartments, bioelec-trical impedance analysis (BIA) was performed usingportable equipment (BODYSTAT  1500, Bodystat LTD, Isleof Man, British Isles). Fat, muscle mass and total body water were determined and expressed as relative values to totalbody weight. Arterial blood was taken following conven-tional techniques. Gas analyses were performed (BeckmanCoulter, Synchron Cx9Po, Germany). Forced spirometry(Sibel, Barcelona, Spain), static lung volumes, airwayresistance, and carbon monoxide diffusing capacity (Mas-terlab, Jaeger, Wu ¨rzburg, Germany) were assessed in allpatients. 15 e 17 Inspiratory and expiratory muscle strengthwere assessed by determining maximal respiratory mouthpressures during voluntary manoeuvres. Patients wereinstructed to carr y out maximal respiratory efforts withoccluded airway. 18 Maximal inspiratory pressure (PI max ) wasmeasured from pulmonary residual volume (RV), andmaximal expiratory pressure (PE max ) from total lungcapacity (TLC). The best value of three reproduciblemanoeuvres (difference  < 5%) was included in the analysis.( P  max  Morgan Medical, Gillingham, Kent, UK). PI max  andPE max  values were assessed both in absolute (cmH 2 O) andrelative pressure values according to reference valuesreported by Morales and colleagues. 19 A hand dynamometer (JAMAR dynamometer; Preston,Jackson, MI, USA) was used to record maximal voluntaryhand grip strength (HGS, in kg) of the finger flexors in boththe dominant and non-dominant hand (HGS d  and HGS nd respectively) during three consecutive manoeuvres sepa-rated by a 3-minute rest. The maximal value of thereproducible manoeuvres was used for the analysis. Abso-lute and relative values were analysed in relation toreference values. 20 Statistical analysis All numerical values are expressed as the mean    SD. Asa case control study the characteristics analysis was con-ducted using the  t  test (for quantitative variables of normaldistribution), the Kruskal e Wallis test (for quantitativevariables of non-normal distribution) or   c 2 (for qualitativevariables). Normal distribution was tested using a Shapir-o e Wilk test. The variables corresponding to muscle func-tion and body composition were included in the analyses asdependent variables. Age and lung function tests wereanalysed as independent variables. An unconditionedmultivariate logistic regression model was used to obtainthe association between muscle weakness and exacerba-tion, after adjusting for potential confounders. 21 A  p  valueof  < 0.05 was deemed to be significant. Results A total of 121 former or currently smoking patients (92%males) were included in the study. As part of the usualoutpatient treatment, all patients received some inhaledbronchodilator therapy (formoterol, salmeterol, albuterol,tiotropium, ipratropium), 5% received oral theophylline,and 15% received inhaled steroids. No patient receivedsystemic steroid therapy on a regular basis. At baseline, nopatient presented chronic respiratory failure (defined asPaO 2 < 60 mmHg), and none of them qualified for long-termoxygen therapy. Ten patients, however, showed PaCO 2 above 45 mmHg.General characteristics of the study groups are sum-marised in Table 1. Seventy-seven patients were at stableclinical conditions, whereas 44 patients were admitted tothe hospital due to acute exacerbation of COPD. Differ-ences in body composition were associated with history ofmultiple hospital admissions whereas patients under firsthospital admission showed fat and fat-free mass compa-rable to the stable non admitted COPD group. Collectively,there were differences between the four groups in someprincipal pulmonary function variables. Patients withhistory of multiple admissions and present acute exacer-bation, disclosed greater air trapping (%RV) and lower diffusing capacity for CO (both TL CO  and K  CO ) compared tothe COPD patients without admissions (  p  <  0.05 each).Table 2 shows that muscle weakness was strongly asso-ciated with the past and current exacerbations of COPD.Fig. 1 shows a significant decrease of both respiratory andperipheral muscle strength in all patient groups. After adjusting by GOLD stage (FEV 1 ), muscle weakness showeda significant association with two covariates: number ofpast admissions and current hospital admission, as indi-cated in Tables 2 e 4. Discussion The present study confirms that dysfunction of both respi-ratory and peripheral muscles is highly prevalent in patientswith COPD, even during stable clinical conditions. This isprobably the first report identifying an association betweenrisk for hospital admission due to exacerbations and base-line muscle function, irrespective of body weight and BMI.1898 J. Vilaro´ et al.  This association between muscle weakness and risk ofhospitalisation remained significantly increased after adjustment by the degree of airflow obstruction.Muscle dysfunction in patients with COPD is not merelya cosmetic description. Muscle function is relevant from theclinical point of view as it is associated with increasedsymptoms (dyspnoea and discomfort in legs), impairedphysical performance (e.g., decrease in exercise capacity),reduced health status, and increased risk of mortality, 2 independent of traditional markers of COPD mortalitysuch as baseline lung function, age, and cigarettesmoking. 6,7 Surprisingly, we identified one study analysingthe potential role of muscle dysfunction as a risk factor  ofsevere exacerbations of COPD and hospital admissions. 11 Our results reported so far suggested a previouslyunrecognised association in which muscle dysfunction is notonly present in stable clinical conditions but associatedwith the risk of hospital admissions. Table 1  General characteristics of the study population.Stable COPD Acute exacerbation of COPDNo previousadmissionsWith multipleadmissions a No previousadmissions a With multipleadmissions a Patients  n  (%) 50 (41) 27 (22) 17 (14) 27 (22)Age Yrs 66  7 68  7 67  8 65  9  Anthropometrics Weight Kg 75  13 76  16 71  8 78  17BMI kg/m 2 27  4 27  5 25  3 28  5TBW % 54  4 57  3 a 57  3 a 55  4FM % 28  9 18  3 b 27  6 22  6 a FFM % 20  3 20  1 18  4 22  6 a Pulmonary function FEV 1  % pred 49  17 42  15 37  16 37  13FVC % pred 72  13 68  15 62  23 59  19TLC % pred 110  20 108  16 112  23 110  21RV % pred 162  55 108  16 178  69 209  65 b TLco % pred 63  23 54  19 60  11 47  21 a Kco % pred 75  21 72  26 63  20 58  25 a PaO 2  mmHg 74  12 71  10 64  9 63  16PaCO 2  mmHg 39  5 41  5 42  10 43  6 Smoking exposure Smoking, % Current/former 34/66 4/96 44/56 33/67Pack-year 29  20 34  8 49  42 a 30  9  Abbreviations:  (BMI): body mass index; (TBW): Total body water; (FM); fat mass; (FFM): fat-free mass; (FEV 1 ): forced expiratory volumein the 1st second; (FVC): forced vital capacity; (TLC) total lung capacity; (RV): residual volume; (Tlco, Kco): transfer capacity for CO. a  p < 0.05 ;  p  values correspond to comparisons with the stable COPD with no previous hospital admission group. b  p < 0.01;  p  values correspond to comparisons with the stable COPD with no previous hospital admission group. Table 2  Function of peripheral and respiratory muscles as assessed by maximal voluntary contraction manoeuvres accordingto both clinical status and history of hospital admissions.Stable COPD Acute exacerbation of COPDNo previousadmissionsWith multipleadmissions a Firstadmission a With multipleadmissions a Patients,  n  (%) 50 (41) 27 (22) 17 (14) 27 (22) Peripheral muscles Dominant HGS %pred (%n) 73  13 (31) 64  12 b (58) 52  22 c (70) 58  18 c (68)Non-dominant HGS %pred (%n) 71  12 (50) 62  11 b (58) 53  19 b (67) 55  18 b (82) Expiratory muscles PE max  %pred 77  21 83  21 56  18 b 52  26 b Inspiratory musclesPI max  %pred 85  24 71  18 a 53  19 c 63  28 b  Abbreviations:  (HGS): hand grip strength, dominant and non-dominant; (PImax): Maximal inspiratory pressure measured at the mouth(Mu¨ller manoeuvre); (PEmax): maximal expiratory pressure measured at the mouth (Valsalva manoeuvre). Values correspond to thepercentage of predicted values and in (), the patients incidence of muscle dysfunction, under 70% of predicted, for each study group. a  p < 0.05;  p  values correspond to comparisons with the stable COPD with no previous hospital admission group. b  p < 0.01;  p  values correspond to comparisons with the stable COPD with no previous hospital admission group. c  p < 0.001;  p  values correspond to comparisons with the stable COPD with no previous hospital admission group. Muscle dysfunction and risk of exacerbation in COPD 1899  The present multicentre study offers novel information,including a particular selection and group assignment of thepatients. We analysed former smokers with COPD whoshowed a preserved body weight and were withoutcomorbidity (known or detected during the clinical assess-ment processes), regular use of alcohol or sedatives, anddomiciliary oxygen therapy. These selection criteria allowus to summarise the results in three main concepts, asfollows.  The first concept  is that patients with stable COPDwithout hospital admissions had a high prevalence ofrespiratory and peripheral muscle dysfunction as assessedby strength of inspiratory, expiratory and peripheralmuscles (Table 2). These data confirm previous knowledgethat skeletal muscle dysfunction is among the frequentextrapulmonary manifestations even in stable COPD. 4 Thesecond concept  derived from our study is that, acuteexacerbation of COPD associates with an increase in bothprevalence and severity of global muscle dysfunction (Table4). It is reasonable to postulate that this additionalimpairment in muscle function is associated with theinflammatory burst and therapy of exacerbations. In fact,we recently showed that COPD patients who requireadmission for exacerbation suffer a global, progressive andlinear deterioration of muscle function. 10 The  thirdconcept  deals with the evidence that prevalence andseverity of respiratory and peripheral muscle dysfunctionremain elevated even while recovering clinical stability(Table 3). These data are consistent with the study fromother cohort by Gonzalez et al., 11 who were able todemonstrate that at hospital discharge, noninvasivelymeasured respiratory muscle overload were associated withan increased risk of hospital readmission for exacerbationin patients with moderate-to-severe COPD. Despite theseinformation, the ultimate cause of muscle dysfunction hasnot yet been determined in either stable or exacerbatedCOPD, but our study clearly demonstrates that muscleweakness strongly associates with the risk for hospital-isation due to exacerbation, as discussed below.Exacerbation of COPD represents not only a worsening ofairflow obstruction but also increased respiratory andsystemic demand in a host r eceiving treatment and withlimited ventilatory reserve. 22 With regards to inspiratory 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 0 1 Stable COPD without history of admissions Stable COPD with history of multiple admissions First admission due to exacerbation of COPD Exacerbated COPD with multiple admissions    P  r  e  v  a   l  e  n  c  e  o   f  m  u  s  c   l  e   d  y  s   f  u  n  c   t   i  o  n    (  v  a   l  u  e  s   <   7   0   %   p  r  e   d   ) Dominant hand Non-dominant hand Expiratory muscles Inspiratory muscles Figure 1  The graph represents the proportion of patients suffering muscle dysfunction determined by a decrease under 70% ofthe predicted values. The prevalence of respiratory muscle dysfunction is higher in exacerbated patients but for peripheralmuscles, the prevalence is more notorious in hospital multiple admitted patients. Table 3  Crude and adjusted associations between muscle dysfunction and risk for severe exacerbations in stable COPDpatients without hospital admissions vs. stable patients with multiple admissions.Univariate logistic regression Multivariate logistic regression a Crude OR (95% CI)  p  Adjusted OR (95% CI)  P Peripheral muscle weakness Dominant HGS Lower than 70%pred 5.4 (2.0 e 14.4)  < 0.001 6.0 (2.0 e 17.9)  < 0.001Non-dominant HGS Lower than 70%pred 2.1 (1.2 e 8.3) 0.12 1.7 (0.6 e 4.7) 0.30Expiratory muscle weaknessPEmax Lower than 70%pred 0.88 (0.3 e 2.5) 0.81 0.6 (0.2 e 2.2) 0.55Inspiratory muscle weaknessPImax Lower than 70%pred 3.6 (1.4 e 9.4)  < 0.01 3.2 (1.1 e 9.0)  < 0.05  Abbreviations:  (HGS): hand grip strength; (PImax): Maximal inspiratory pressure measured at the mouth (Mu¨ller manoeuvre); (PEmax):maximal expiratory pressure measured at the mouth (Valsalva manoeuvre). a Adjusted by FEV 1 . 1900 J. Vilaro´ et al.

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