慢性阻塞性肺疾病骨骼肌功能下降的调查分析与机制探讨
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摘要
背景:慢性阻塞性肺疾病(COPD)是一种以气流受限不完全可逆为特征的慢性气道炎症反应性疾病。然而,COPD不仅仅是局限于肺部的疾病,而是一种全身多系统性、慢性炎症反应性疾病。骨骼肌消耗及功能失调(SMD)作为COPD全身效应的主要表现之一,常常始于疾病的早期,是患者活动受限的主要原因之一,严重影响患者的生活质量;SMD同时也是影响COPD本身严重程度的重要因素之一,与患者的死亡率密切相关。COPD患者SMD的发生机制已经成为国外研究的热点。近年来的观点认为,COPD患者SMD的发生与全身慢性炎症反应、营养不良、肌肉废用性萎缩、激素的使用等机制有关,但每一种理论似乎均不能完全解释COPD患者SMD的发生。全面准确评估骨骼肌功能是探索SMD发生机制的基础,骨骼肌功能的全面评估包括耐力评估和收缩力评估。股四头肌作为外周骨骼肌的代表,便于检测,是COPD外周骨骼肌功能检测和研究的主要肌肉。传统的股四头肌收缩力的评估需要依赖受试者的主观努力,属于主观用力依赖的检测方法。近年来采用磁刺激股神经诱发股四头肌的颤搐张力,检测肌肉的被动收缩力,不依赖受试者的主观努力,属于无需主观用力的方法。建立本地正常老年人群(与COPD患者年龄匹配的人群)外周骨骼肌功能的参考值,探索COPD患者外周骨骼肌功能异常的发生率、严重程度,以及相关的危险因素,对防治COPD患者外周骨骼肌功能异常具有重要的理论和临床应用价值。
目的:建立老年健康者外周骨骼肌(股四头肌)功能检测指标的正常值,调查稳定期COPD患者外周骨骼肌的功能状态,探索COPD患者SMD发生的相关机制;同时,比较三种不同的股四头肌功能检测方法的优缺点,为实践中选择检测方法提供依据。
材料与方法
一.研究对象:
研究对象包括稳定期COPD患者和年龄匹配的正常对照者。所有COPD患者(COPD组)均来自广州呼吸病研究所(国家重点实验室)门诊。COPD的诊断根据GOLD指南的标准,通过肺功能检查明确诊断。选择稳定期的患者,近两个月来无急性发作。通过详细询问病史、体检、心电图、胸片和血液生化检查等排除心血管疾患、风湿性疾病、神经肌肉疾病等伴发病。正常对照组受试者来自于广州医学院第一附属医院健康体检的同龄健康志愿者。
二.方法:
1.股四头肌力量评价和肌电记录方法:股四头肌功能测量技术按照Polkey等所述的方法,受试者坐在一张特制的椅子上,椅子的靠背可以活动,竖直或平放,受试者膝关节呈90度弯曲,悬垂于椅子末端。用一条无弹性皮带连接脚踝与应力测量器(测量范围0-150 kg)。皮带一端置于脚踝上1~2cm处,与脚踝垂直,另一端通过负荷感受器与应力测量器相连。每次测试前用标准力量定标。股四头肌体表肌电图(SEMG)的检测分别于股外侧肌肌腹、股直肌肌腹、股内侧肌腹表面安放测试电极,参考电极置于膝关节处。整个测试过程中必须确保受试者的膝关节角度不能改变,固定脚踝的皮带及力量负荷感受器应当始终与地板保持平行水平。然后进行下列检测
2.股四头肌功能检测的程序:股四头肌的功能检测项目共包括以下三项:磁刺激股神经诱发的股四头肌肌颤搐张力(TwQ)、股四头肌最大主动收缩力(QMVC)和耐力时间(Tf)。
2.1磁刺激诱发的肌颤搐张力(TwQ):方法参照Hamneg?rd等所述:将“8”字形的磁刺激条放置于股三角内股动脉外侧,同步记录TwQ及磁刺激范围内相应的复合肌肉动作电位(CMAP)。磁刺激股神经诱发股四头肌被动收缩的所产生的TwQ作为力量衡量指标、CMAP幅度作为肌电衡量指标。为了避免肌肉收缩后对TwQ的强化效应,首次磁刺激前受试者安静休息20分钟。首先以100%刺激强度时诱发的股四头肌颤搐张力(TwQ100%)最大处的部位定位并做好标记,以保证在整个磁刺激过程中的位置固定。然后分别用40%、60%、80%、90%和100%的刺激强度对受试者进行检测。
股四头肌被动收缩力的评估标准以最大肌颤搐张力(TwQmax)为准。TwQmax的判断标准为:随着磁刺激强度的逐步增加,所诱发的肌肉被动收缩力(即TwQ)及肌肉复合动作电位(即CMAP)出现平台。所有的131例受试者中,TwQ及CMAP均随着刺激量的增加而增加,其中的121例(对照组54例、COPD组67例)TWQ及CMAP最终出现平台,即检测到TwQmax。对于能检测到TwQmax的121例受试者,以三次_(100%)磁刺激强度下所诱发的TwQ(即TwQ_(100%))的平均值作为最终TwQmax的结果。有10例,包括对照组6例(男性2例,女性4例)、COPD患者组4例(均为男性)未检测到TwQmax,即随着刺激强度的增加,没有观察到TwQ或CMAP平台的出现。此10例受试者中的9例体重指数明显高于其他受试者(24.5~31 kg/m~2), TwQ_(100%):QMVC的比值均<0.16;另外一例其体重指数正常,但TwQ_(100%)的最大值(25kg左右)明显高于其他所有受试者,TwQ_(100%):QMVC的最高比值为0.58,每次诱发的TwQ_(100%)值不稳定、变异度大(变异率大于20%)。因此,此10例受试者未纳入TwQmax的统计分析。
2.2股四头肌最大主动收缩力(QMVC)的测试:受试者端坐体位,膝关节与髋关节同时呈900,尽最大力量向前伸腿产生的力量即QMVC。通过电脑屏幕的同步显示,受试者可以观察自身的力量曲线,同时鼓励受试者,使其每次尽最大力量,直到QMVC达到平台,没有再增加趋势。每次QMVC持续3-5秒,中间间隔大约45-65秒,防止肌肉疲劳,具体间隔时间结合个体受试者的自觉症状及要求进行调整。重复检测至少有连续三次QMVC重复性较好(各数值之间差异性<10%),这三次中的最大数值即被认为QMVC。
2.3耐力测试:耐力是指在60%的QMVC时等长收缩所持续的时间(秒)。目标力量设置用每个受试者自身QMVC的55%~65%,在电脑屏幕上显示。受试者持续用力,使力量曲线维持在上述范围。当力量低于50%的QMVC时,允许小于3秒钟的放松,然后再努力维持力量曲线在上述范围。在持续用力过程中如果力量下降低于50%的QMVC时间大于3秒,则视为耐力测试结束。最后结果采用总的用力持续时间之和,即达到疲劳所需要的总时间为耐力时间(Tf)。
2.4数据采集和分析:表面电极和应力测量器的信号与放大器连接,然后在数据采集系统(PowerLab 8/16SP)的支持下以2 Khz(磁刺激时采样频率为10Khz)的采样频率同步记录并保存于苹果电脑中,待后以Chart 5.2软件分析。表面肌电信号以计算均方根(RMS-100ms)用来衡量肌电幅度,计算M波的正负峰值差以衡量CMAP幅度。
3.营养指标的评估:采用多参数营养不良评分表(MNI)对患者的营养状况进行总体评价。此评估主要由血液生化指标和人体测量学指标组成。前者包括血清白蛋白(ALB)、转铁蛋白(TFR)、甘油三脂(TRG)及胆固醇(CHO);后者包括身高、体重、肱三头肌皮下脂肪厚度(TSF)、上臂中点周径(MAC)、上臂中点肌肉周径(MAMC)、腹围等。根据身高体重计算受试者的体重指数(BMI)及标准体重(IBM)。
4.股部肌肉体积的估算:采用间接指标。以股部中点周径及皮下脂肪的测量值,根据公式推算出股部中点的肌肉周径(MTMC)。
5.肺功能测试:所有的受试者均进行常规肺功能测试,测试项目包括FEV1、FVC、FEV1/FVC(%)、PEF等肺功能指标。COPD患者的肺功能指标需要观察吸入支气管舒张剂前后的对比,在排除合并哮喘后,则选取支气管舒张剂吸入后的数值。
6.日常活动评分:日常活动(PA)评分参照Serres等评分方法,对受试者进行问卷调查,共涉及5大项目:职业、日常活动、体育运动、业余爱好、以及除外睡眠和运动以外的业余时间活动,具体共由19项组成,每一项按强度及频度分级,最后算出总分。
7.血液中炎症因子的检测:共检测8种细胞因子和炎症介质。用酶联免疫分析(ELISA)法检测以下7种细胞因子:肌抑制素、肿瘤坏死因子(TNF)-α、TNF样凋亡诱导因子(TWEAK)、表面活性蛋白D(SPD)、C反应蛋白(CRP)、白介素(IL)-1β及IL-6。用细胞免疫化学(ICC)法检测核因子KppaB(NF-κB)的表达:分别检测外周血液中单核细胞及中性粒细胞中核因子NF-κB的表达,以半定量方法对ICC检测结果进行分析,取两种细胞对NF-κB表达的平均值作为最后结果。
三.研究流程
开始测试时间为清晨(7:30-8:30分),受试者空腹,留取静脉血标本6ml, 2ml不加抗凝剂,用以检测血清蛋白及血脂;4ml抗凝血离心后用以检测血浆中及血细胞内的细胞因子的表达。血标本暂时保存于4℃冰箱,4小时内进行初步处理,待后进一步处理。人体学测量亦在空腹进行。早餐后进行股四头肌功能测试,首先进行磁刺激检测,然后依次进行QMVC测试及耐力测试,每项功能测试前受试者分别安静休息20分钟。最后(或当日下午)进行肺功能测试及日常活动评分问卷调查。
四.统计学处理和结果分析
应用SPSS10.0统计软件分析。计量资料以±s表示,分类变量以百分比(%)表示,以P<0.05为差异有统计学意义。COPD组与对照组之间比较采用非配对t检验及卡方检验。主客观测试方法变异度的比较采用两种方法:(1)个体间变异度的比较,以变异系数进行评估,变异系数[CV=(标准差/均数)×100%];(2)重复测量数据变异度的比较,分别以三次重复测量数据之间的变异率进行评估,变异率=[(最大值-最小值)/(最大值+最小值)×100%]。两组内的股四头肌功能检测的三项指标与其相关因素之间均采用逐步回归分析法;股四头肌功能检测指标的收缩力和耐力之间,以及主动与被动两种收缩力之间均采用简单线性相关分析。
结果
1.一般状况:正常对照组60例,其中男性21例,女性39例;COPD组71例,其中男性54例,女性17例,性别比例存在差异性(P<0.01)。两组受试者的平均年龄分别为:正常对照组(63.98±5.77)岁,COPD患者组(65.17±6.80)岁,组间比较无差异性(P=2.29)。两组受试者身高的平均值分别为:正常对照组(161.03±7.80)cm、COPD患者组(162.22±7.14)cm,组间比较无差异性(P=0.36)。所有受试者均未参加过任何康复或体能训练,未曾接受营养支持治疗。
2.肺功能测试结果:正常对照组每一位受试者肺通气功能测试的各项指标均在正常范围内,其中第一秒用力呼气容积占预计值百分比(FEV1%pred)为(97.10±8.90)%,而COPD患者的FEV1%pred为(37.76±14.93)%,两组间比较有显著差异性(P<0.001)。根据Gold分级标准,本研究中58%的COPD患者肺功能下降的严重程度属于中重度。
3.营养指标评分:多参数营养不良评分(即MNI)结果显示:COPD组患者的MNI为(7.75±3.86)分,正常对照组的MNI为(1.13±0.96)分,两组间比较有显著差异性(P<0.001),显示出COPD患者的营养状况普遍下降。
4.肌肉体积评估:正常对照组MTMC的平均值为(43.19±3.55)cm,COPD患者组其平均值为(37.77±3.73)cm,两组间比较有显著差异(P<0.001),显示出COPD组患者的股部肌肉体积明显下降。
5.日常活动评分:正常对照组的PA评分的平均值为(7.97±1.21)分,COPD患者组PA评分的平均值为(5.25±1.38)分,两组间比较有显著差异性(P<0.001),显示出COPD组患者的日常活动明显减少。
6.肌肉功能测试结果及方法学对比:
6.1肌肉功能测试结果
6.1.1检测结果:正常对照组男性的QMVC为(42.06±7.61)kg、耐力时间为(81.09±22.58)秒、TwQmax为(13.91±3.94)kg,而COPD患者组男性的QMVC为(23.26±5.74)kg、耐力时间为(51.13±18.73)秒、TwQmax为(7.25±2.29)kg;女性正常对照组的QMVC为(29.24±4.58)kg、耐力时间为(83.44±23.64)秒, TwQmax为(7.75±1.75)kg,而女性COPD组的QMVC为(15.55±4.25)kg、耐力时间为(56.31±15.49)秒,TwQmax为(4.18±0.89)kg;各组间比较均有显著差异性(P<0.001)。
以正常对照组受试者肌肉功能三项检测指标的检测值为因变量,以相关因素作为自变量,计算出正常健康老龄者(58-76岁)的股四头肌功能指标回归方程(正常值预计方程)如下: QMVC (kg)=0.383+ 7.278×性别+1.967×PA评分(分) +0.257×体重(kg) Tf (秒)=2.143×MTMC(cm)+11.467×PA评分(分)+1.244×体重(kg)-34.759×性别-162.478 TwQmax (kg)=0.370×身高(cm) + 0.898×PA评分(分)-56.775
6.1.2股四头肌功能下降的发生率
以对照组受试者肌肉功能检测值的95%可信区间的下限为标准判断,94%的患者存在主动收缩功能(即QMVC)下降;78%的患者存在耐力功能(即Tf)下降;90%的患者存在被动收缩功能(即TwQmax)下降。所有COPD患者中,任何一项出现异常的发生率为94%,同时存在QMVC、Tf及TwQmax三项指标均下降的发生率为59%。
根据股四头肌功能正常值预计方程95%可信区间的下限为标准判断,95%的患者存在QMVC下降;45%的患者存在Tf下降;85%的患者存在TwQmax下降。所有COPD患者中,任何一项出现异常的发生率为95%,同时存在QMVC、Tf及TwQmax三项指标下降的发生率为46%。
6.1.3股四头肌功能下降的严重程度
以正常对照组肌肉功能检测的实测值为基准,男女分层比较显示:男性COPD患者的QMVC平均下降45%、耐力时间(即Tf)平均下降37%,TwQmax平均下降47%;女性COPD患者的QMVC平均下降48%、Tf平均下降33%、TwQmax平均下降44%。
根据健康老龄者股四头肌功能正常值的预计方程,COPD患者的QMVC平均占正常预计值的65%、Tf平均占正常预计值的73%,TwQmax平均占正常预计值的67%。
6.1.4肌肉功能下降的特点:就三项测试指标在COPD患者中下降的严重程度进行对比,结果显示:主动收缩力(即QMVC)平均下降46%、被动收缩力(即TwQmax)平均下降45%、耐力时间(即Tf)平均下降为35%。总体评价:收缩力下降程度较耐力下降的严重程度更显著。
6.2主客观测试方法变异度的比较
6.2.1重复测量数据变异度的比较
对于主客观测试方法重复性的评估,以三次重复测量数据变异率进行对比。组内男女分层比较,TwQmax和QMVC的变异率分别为:正常对照组(男性2.3 v 3.3%;女性3.4% v 3.7%);COPD患者组(男性3.9% v 8.5%;女性3.3% v 5.1%),显示TwQmax的变异率低于QMVC,即前者的重复性高于后者;但所有的变异率均<10%。
6.2.2个体间变异度的比较
对于个体间变异度的比较,以变异系数衡量。剔除未达到最大刺激强度的受试者,就TwQmax及QMVC进行对比,二者的变异系数分别为:正常对照组(男性27% v18%;女性23%v15%);COPD患者组(男性32% v 24%;女性21% v 27%)。组内男女分层分析结果显示:对照组的男性及女性、COPD患者组的男性,此三组中TwQmax的变异系数均高于和QMVC,即TwQmax在个体间的变异度高于QMVC;仅在COPD女性中,TwQmax在个体间的变异度低于QMVC。此结果显示出TwQmax在个体间变异度普遍高于QMVC。
7.细胞因子
细胞因子检测结果分别为:SPD(ng/ml):正常组(31.97±5.54)、COPD组( 47.52±17.26 ) ; Tweak (pg/ml) :正常组( 447.57±84.25 )、COPD组(583.39±241.50);肌抑制素(ug/ml):正常组(31.76±9.39)、COPD组(48.71±21.01);TNF-α(pg/ml):正常组(6.23±4.49)、COPD组(13.91±2.86),以上4种细胞因子在COPD组与正常对照组之间比较,均有显著差异性(各P<0.001)。另外4种包括IL-6、IL-1β、CRP及NF-κB也在COPD组有升高趋势,但统计分析与正常对照组之间无显著差异(各P>0.05)。细胞因子筛查结果显示:所有检测的8项细胞因子均在COPD组升高,但其中仅有4种达到统计学意义。
8.相关分析
8.1逐步回归分析
正常对照组的QMVC与性别、PA评分、体重显著相关(R~2 =0.61,p<0.001);耐力时间与PA评分、MTMC、体重及性别相关(R~2 =0.58,p<0.001);TwQmax与身高及PA评分相关(R~2 =0.67,p<0.001)。
COPD患者组QMVC的实测值与性别(0.513)、肺功能FEV1%pred(0.240)、肌抑制素(-0.231)、SPD(-0.149)、MN(I-0.168)及TWEAK(-0.192)相关(R2=0.89,p<0.001);耐力时间与FEV1%pred(0.421)及TNF-α(-0.289)相关(R2=0.25,p<0.001);而TwQmax与以上各因素均无相关性。逐步回归方程的β系数显示:FEV1%pred在COPD患者的QMVC指标中为仅次于性别因素的相关因子;在耐力测试指标中FEV1%pred的β值也高于TNF-α。
8.2不同的股四头肌功能评估方法之间的线性相关分析
收缩力与耐力之间:正常对照组及COPD患者组的两种收缩力与耐力指标之间均无相关性。就主动收缩力(即QMVC)与Tf之间的相关系数为例,其在正常对照组为r=0.106(p=0.421)、在COPD患者组为r=0.225(p=0.06)。
被动与主动两种收缩力之间:剔除没有达到TwQmax的受试者,分析TwQmax与QMVC之间的相关性,结果显示:在54例正常受试者中二者显著正相关(r=0.793, p=0.000),在67例COPD患者中二者也呈正相关(r=0.396, p=0.001);TwQmax与QMVC之间的比值在正常对照组为0.29、在COPD患者组为0.32。
结论
1.正常老年(58-76岁)健康者股四头肌功能检测指标的预测公式为: QMVC (kg)=0.383+ 7.278×性别+1.967×PA评分(分) +0.257×体重(kg) Tf (秒)=2.143×MTMC(cm)+11.467×PA评分(分)+1.244×体重(kg)-34.759×性别-162.478 TwQmax (kg)=0.370×身高(cm) + 0.898×PA评分(分)-56.775
2.与同龄健康者相比,94%的COPD患者存在不同程度的股四头肌功能下降,半数以上患者的肌肉功能严重下降;其中,收缩功能较耐力功能下降的程度更为显著。
3.COPD的气流阻塞程度、全身慢性炎症反应、营养不良、肌肉萎缩等均是导致SMD发生的主要危险因素,其中,气流阻塞与SMD的发生关系最密切。支持COPD患者SMD的发生与多种因素有关的观点。
4.慢性系统性炎症反应作为COPD患者SMD发生的主要危险因素之一,其中的细胞因子SPD、肌抑制素、Tweak及TNF-α在COPD中显著性升高,是COPD发生SMD的候选生物标记物和干预切入点。
5.股四头肌功能检测的三种方法各有其优缺点。TwQmax虽然无需受试者的主观配合,可用于无法主动配合的受试者,重复性好,有利于动态监测;但其在个体间变异性较大,不利于群体之间的比较。QMVC检测方法较简单,个体间变异度小,可以较准确地反映肌肉的收缩功能;但需要受试者配合,重复检测的变异率稍大于磁刺激诱发的TwQmax。耐力评估方法较复杂、持续时间长,对受试者主客观配合的要求高,不适宜作为常规检测。
Background Chronic obstructive pulmonary disease (COPD) is a multiple component disorder with systemic effects. Skeletal muscle dysfunction (SMD) is one of the most important systemic manifestations of COPD. SMD has been recognized as a contributing factor related to reduced exercise capacity, impaired quality of life, and increased mortality and health care utilization. There is increasing concerns on the potential role of peripheral muscles dysfunction in COPD as it might be a potential site of intervention for improving patient’s functional status. A variety of mechanisms related to SMD in COPD have been postulated, such as systemic inflammation, malnutrition, muscle disuse and atrophy, etc; while none of the above mentioned mechanisms could fully explain SMD in COPD. Quadriceps function assessment was used in majority of the studies for assessment of peripheral skeletal muscle function as it is readily accessible and is a primary locomotor muscle. Accurate assessment of skeletal muscles function is important for investigation of the mechanism of SMD in COPD. Comprehensive evaluation of muscles function should include the assessment of both of strength and of endurance capabilities. The conventional test for assessment of quadriceps strength is the maximal volitional contraction (QMVC), which is depending on subjects’volitional effort and affected by learning effects. In the past twenty years, magnetic stimulation of femoral nerve has been employed to assess quadriceps strength non-volitionally, which is not influenced by subjects’effort and co-operation. Furthermore, proper evaluation of the prevalence and severity of SMD in COPD relies also on the proper control data from the age-matched normal subject. So, adequate normal values of quadriceps function in age-matched healthy elderly were important for the study.
Objective The purposes of the study are to establish normal predicted values for quadriceps muscle function tests in healthy elderly, which can provide proper control data for age-matched COPD patients, to evaluate the prevalence and severity of SMD in patients with COPD, and to explore the related risk factors. Meanwhile, the methods of quadriceps function testing were compared in order to provide evidence for selection of testing for clinical evaluation.
Materials and Methods
1. Study subjects
Seventy-one patients with stable COPD and 60 age-matched healthy volunteers were recruited for the study. Patients were recruited from outpatients’clinics of Guangzhou Institute of Respiratory Disease (State Key Lab of Respiratory Disease) during the period from Mar 2007 to Oct 2007. The diagnosis of COPD was according to the criteria recommended by the GOLD guideline. Significant co-morbidities were excluded by medical history, physical check-up and conventional lab investigations. Subjects exclusion criteria included history of exacerbation in the preceding month, co-morbidities of cardiac, rheumatologic or neuromuscular disorders or unwilling to participate in the study. Subjects in control group were recruited from health check-up department of First Affiliated Hospital of Guangzhou Medical College.
2. Quadriceps function assessment
Quadriceps function test was performed with the technique described by Polkey et al, with a specially designed chair from which the back was removed and laid flat. The test was performed with the subject’knee flexed at 90 degree over the end of the chair. The ankle of the dominant leg was placed in an inextensible strap that was connected to a strain gauge, and the strain gauge was calibrated after each test with weights of known amounts. The force output and compound muscle action potential (CMAP) of surface electromyography (SEMG) was recorded simultaneously. SEMG was recorded for quadriceps muscles of rectus femoris, vastus lateralis and vastus medialis. Quadriceps muscle functional test included the three items: twitch tension (TwQ) evoked by magnetic stimulation of the femoral nerve, strength of maximal volitional contraction (QMVC), and endurance time.
2.1 TwQ
TwQ was induced by magnetic stimulation of the femoral nerve. Subjects were studied supine on the apparatus, with knee joints flexed at 90 degree over the end of the apparatus. Femoral nerve stimulation was performed using a 70-mm figure-of-eight coil powered by a Magstim 200 stimulator. The coil head was positioned high in the femoral triangle just lateral to the femoral artery. Minor positional adjustments were made to the coil whilst simultaneously monitoring quadriceps force during stimulation to determine the optimum position. TwQ evoked by stimulation at 100% intensity of the stimulator power output (TwQ_(100%)) was used to determine the best spot. The best spot that resulted in the largest TwQ_(100%) was identified and marked in order that the same position was used throughout the range of stimulator outputs. To avoid twitch potentiation, there was a rest period of 20 minutes before the start of the magnetic stimulation. After identifying the best location, stimulations of varying intensities were administered at a stepwise increment in the stimulator’s output. For each subject, stimulation was administrated at 40%, 60%, 80%, 90% and 100% intensity of the stimulator power output, respectively.
Quadriceps non-volitional strength was assessed with the maximal TwQ (TwQmax). To determine whether TwQ reached to the TwQmax, a near plateau in TwQ and CMAP with increasing power output were observed, indicating maximal depolarization of the femoral nerve. In the present study, TwQmax was achieved in 121 subjects (54 normal subjects and 67 patients), and the result of TwQmax was finally determined as the mean of three reproducible TwQ_(100%) for these subjects. TwQmax was not achievable in 10 participants (6 normal subjects and 4 patients), as a plateau in either TwQ or CMAP amplitude was not reached with the increasing intensity of the stimulator power output up to 100%. Compared with the 121 subjects mentioned above, 9 of the 10 participants had higher BMI (24.5~31 kg/m~2) and a lower ratio of TwQ100%:QMVC (<0.16); the remain one subject had a normal BMI but presented a much higher TwQ100% (25kg), with a higher variability of TwQ100%(>20%). Therefore, the data from the 121 subjects was used for TWQmax in statistical analysis, excluding the data from the 10 subjects.
2.2 QMVC
QMVC was measured as the subject in an upright position, with hip and knee joints at 90 degree of flexion. Subjects were required to try to extend their dominant leg as hard as possible against the inextensible strap mentioned above. A computer screen was in front of the subjects for the force generated was visible to subject and investigator; so the computer screen was served as a positive feedback mechanism to help subjects to perform the test. Repeated efforts were made with vigorous encouragement until there was no improvement in performance. Efforts were sustained for about 3~5 seconds and rested for about 45~65 seconds between each contraction in an effort to avoiding fatigue. If maximal values were reproducible (<10% variability) for consecutive three times, i.e., the generated strength reached a plateau, the highest value of these three contractions was considered as the QMVC.
2.3 Endurance time
Endurance of the quadriceps was evaluated during an isometric contraction. After 10 minutes of rest following the QMVC maneuvers, subjects were instructed to maintain a tension corresponding to 55%~65% of their own QMVC until exhaustion. The feedback mechanism served by the computer screen helped subjects to maintain the determined submaximal tension. Subjects were strongly encouraged to pursue until tension dropped to 50% QMVC or less for more than 3 seconds (S). Thus, quadriceps endurance was defined as the time to fatigue (Tf), and the time at which the isometric contraction at 60% of maximal voluntary capacity could no longer be sustained.
2.4 Data acquisition
The signal was amplified 1 KHz and passed to PowerLab 8/16 SP hardware and a computer running Chart 5.2 software. SEMG signal from quadriceps was sampled at 2 kHz when QMVC and enduring tests were performed; and it was sampled at 10 KHz when magnetic stimulation of femoral nerve was administered. The amplitude of SEMG in QMVC was determined by calculating the root mean square (RMS-100 ms time constant) over the same contraction period for each muscle. Amplitudes of CMAP were determined by calculating the difference between the peak and the minimum of M-wave amplitudes when TwQ was elicited.
3. Nutritional status assessment
Subject’s nutritional status was evaluated by using a multiparameter nutritional index (MNI), which consisted of anthropometric measurements and visceral proteins level. Anthropometric measurements included body weight, triceps skinfold thickness (TSF), mid-arm muscle circumference (MAMC). Albumin and transferrin plasma concentration was used as visceral proteins store. In addition, serum triglyceride and cholesterol levels were also determined.
4. Quadriceps muscle mass evaluation
Quadriceps muscle mass was evaluated indirectly with midthigh muscle circumference (MTMC), which calculated by mid-thigh skinfold thickness and circumference. MTMC was considered different from other anthropometric indices because midthigh muscles mainly consist of quadriceps, which was the muscle we aimed to study.
5. Spirometric function
Spirometric function was tested in all of the participants. For the patients with COPD, it was required the confirmation of irreversible airflow limitation with post-bronchodilator FEV_1/FVC<70%.
6. Level of daily physical activity
Level of daily life physical activity (PA) was evaluated by using a PA questionnaire adapted for the elderly in China. The original questionnaire on habitual PA consisted of 19 items, scored the past 3 year's household activities, sports activities, and other physically active leisure-time activities and gave an overall PA score. The subjects were asked to describe type of the PA, hours per week spent on it, and period of the year in which the PA was normally performed.
7. Cytokines
Eight cytokines were screened in the present study. Antibody sandwich enzyme-linked immunosorbent assay (ELISA) was used to analyze the level of cytokines in plasma, and immunocytochemistry (ICC) was employed to detect the expression of nuclear factor KppaB (NF-κB) in peripheral blood lymphocytes and neutrocytes.
The concentration of seven cytokines in plasma was determined in duplicate by using ELISA kits. These cytokines included surfactant protein D (SPD), myostatin, tumor necrosis factor (TNF-α), interlukin (IL)-6, IL-1β, TNF-like weak inducer of apoptosis (TWEAK) and C reactive protein (CRP). The expression of NF-κB in peripheral blood lymphocytes and neutrocytes was detected by using immuno-chemistic kits. Semi-quantitative methods were employed to analyze the results of the ICC.
7. Study Procedure
Most of the experiments were performed in the morning. Blood sample collection and anthropometric measurements required subjects to present with an empty stomach. After breakfast, skeletal muscle performance was assessed. Quadriceps function was tested as TwQ was performed firstly, with QMVC and endurance capabilities followed in order. Before each of the items of the functional test, subjects were asked to rest quietly for 20 minutes. At the end of the morning or in the afternoon of the day, spirometric variables were measured, and finally, subjects were asked to respond to the questionnaire of physical activities.
8. Statistical analyses Statistical analysis was performed using SPSS 10.0 statistical package for windows. Measurement data were summarized by mean±SD, and categorical data were summarized by number (percentage). P value <0.05 was considered statistically significant. Two independent-sample t-tests and Chi-Square test were used for univariate testing between the COPD patients and the controls. The variability for both QMVC and TwQmax were investigated by using the following two methods: (1) Intersubject variability, which was determined by calculating the coefficient of variation [CV=(SD/mean)×100%]; (2) Reproducibility of the measurements, which was determined by calculating the variation rate in the repeated measurement data from 3 times, and the variation rate=[(maximum-minimum)/(maximum+minimum)]×100%. In both controls and patients groups, multiple regression models were developed by stepwise method to determine the independent factors respectively contributing to the 3 items of quadriceps performance, i.e., TwQmax, QMVC and endurance. Pearson's correlation analysis was employed to determine the relationship between the variables of strength and endurance time, and between the volitional and non-volitional contraction.
Results
1. Characteristics of the subjects
There were 60 normal subjects in control group, with 21 male and 39 female, and there were 71 patients in COPD group, with 54 male and 17 female; significant difference was observed in gender constituent ratio between the two groups, with P<0.01.
The mean age was (63.98±5.77) years in controls and (65.17±6.80) years in the patients (P=2.29); and the mean height was (161.03±7.80) cm in controls and (162.22±7.14) cm in the patients, respectively, with P=0.36. The results showed that the patients and controls were matched, with respect to age and height. No subjects were receiving nutritional support therapy or had participated in any rehabilitation program previously.
2. Pulmonary function
Spiro metric function test showed that, the mean forced expiratory volume for 1 S (FEV1) was (97.10±8.90) %pred in normal subjects, while it was (37.76±14.93) %pred in COPD patients, and there was significant difference between the two groups (P<0.001). The results showed that patients with COPD had, on average, severe airflow limitation as defined by the GOLD criteria.
3. Nutritional status
Multiparameter nutritional index (MNI) was (7.75±3.86) score in the COPD patients and (1.13±0.96) score in normal subjects, with significant difference between the two groups (P<0.001).The results showed that malnutrition was commonly existed in the patients with COPD.
4. Quadriceps muscle mass
MTMC was (37.77±3.73) cm in the COPD patients and (43.19±3.55) cm in normal subjects, with P<0.001, showing that the patients had decreased muscle mass compared with normal subjects.
5. Level of daily physical activity
PA score was (5.25±1.38) score and (7.97±1.21) score, in the COPD patients and normal subjects, respectively, with significant difference existing between the two groups (P<0.001). The PA questionnaire showed that the patients with COPD had less physical activities in their daily lives compared with the normal subjects.
6 Quadriceps function assessment and methodological issues 6.1 Quadriceps function assessment
When analyzing the results in subgroups of men and women, QMVC was [(23.26±5.74) kg v (42.06±7.61) kg for male, and (15.55±4.25) kg v (29.24±4.58) kg for female]; endurance time was [(51.13±18.73) S v (81.09±22.58) S for male, and (56.31±15.49) S v (83.44±23.64) S for female]; TwQmax was [(7.25±2.29) kg v (13.91±3.90) kg for male, and (4.18±0.89) kg v (7.76±1.75) kg for female] in the patients and in controls, respectively, with each of P<0.001.
6.1.1 Predicted equation for normal values
For the healthy elderly (58~76 years old), the normal values of the quadriceps functional tests were defined as the dependent variant, and the candidate factors related to quadriceps function were analyzed as the independent variant by the stepwise regression correlation models. Consequently, the predicted normal values were given as the following 3 equations: QMVC(kg)=0.383+ 7.278×(sex) +1.967×PA score (score) +0.257×weight (kg) Tf(S)=2.143×MTMC(cm)+11.467×PAscore(score)+1.244×weight(kg)-34.759×(sex)-162.478 TwQmax (kg)=0.370×height (cm) + 0.898×PAscore (score)-56.775
6.1.2 Prevalence of quadriceps dysfunction
According to the lower limit of the 95% confidential interval of the data from the normal subjects, QMVC was impaired in 94% of the COPD patients; Tf was impaired in 78% of the COPD patients, and TwQmax was impaired in 90% of the patients. There were, 94% of the patients with quadriceps dysfunction, in terms of any item of the three indices, and 59% of them with quadriceps dysfunction, in terms of all the 3 items including QMVC, Tf and TwQmax.
According to the lower limit of 95% confidential interval of the predicted normal values showed above, QMVC was impaired in 95% of the patients, Tf was decreased in 45% of them, and TwQmax was impaired in 85% of them. There were, 95% of the patients with quadriceps dysfunction, in terms of any item of the three indices, and 46% of them with all the 3 items including QMVC, Tf and TwQmax.
6.1.3 Severity of quadriceps dysfunction
QMVC was decreased by 45%, Tf by 37%, and TwQmax by 47%, respectively, in male patients, compared with normal male subjects; QMVC, Tf and TwQmax were decreased by 48%, 33% and 44%, respectively, in the female patients, compared with the female controls.
According to the prediction equation for normal values showed above, QMVC was only 65%, Tf was 73%, and TwQmax was 67% of predicted values, respectively, in the COPD patients.
6.1.4 Characteristic of quadriceps dysfunction
With respect to extent of the quadriceps dysfunction, QMVC, Tf and TwQmax were decreased by 46%, 35% and 45%, respectively, compared with normal subjects. Overall, strength showed a larger extent than endurance time in the impairment of the quadriceps functional tests.
In total, quadriceps function was commonly and substantially impaired in the COPD patients, compared with the age-matched normal subjects.
6.2 Variability of volitional and non-volitional techniques
6.2.1 Reproducibility of repeated measurements
Reproducibility of the measurements was assessed by calculating the variation rate of the repeated measurement data from 3 testings. The variation rates of TwQmax and QMVC were [2.3% v 3.3% for male, 3.4% v 3.7% for female] in normal subjects, and [3.9% v 8.5% for male; 3.3% v 5.1% for female] in COPD patients, respectively. According to the results, TwQmax presented a higher reproducibility than QMVC in all of the subjects. However, the variation rates for both TwQmax and QMVC were less than 10% in all of the groups.
6.2.2 Inter-subject variability
Inter-subject variability was assessed with the coefficient of variation (CV). When analyzing subgroups of women or men, CV of TwQmax and QMVC was [28% v 18% for male; 23% v15% for female] in normal subjects, and [32% v 24% for male; 21% v 27% for female] in COPD patients, respectively. The result showed that TwQmax demonstrated greater variability than QMVC in all of the groups except of the female patients group, in which variability was lower for TwQmax than it for OMVC, according to the CV.
7. Cytokines
Concentrations of the 4 cytokines in plasma were elevated in COPD patients as compared with control subjects. The results were showed as following: SPD (ng/ml): (31.97±5.54) vs (47.52±17.26); Tweak (pg/ml): (447.57±84.25) vs (583.39±241.50); myostatin (ug/ml): (31.76±9.39) vs (48.71±21.01); TNF-α(pg/ml): (6.23±4.49) vs (13.91±2.86) (all p<0.05). Another 4 cytokines including IL-6, IL-1β, CRP, and NF-κB were also showed the tendency of elevation in COPD patients comparing with control subjects, but no statistical significance was observed (all p<0.05).
7. Correlations
7.1 Multivariate stepwise regression analysis
In normal control subjects, stepwise regression analysis showed that QMVC could be predicted by sex, PA scores and weight, with R2 of 0.61 (p<0.001); for endurance time, PA scores, MTMC, weight and sex were the predictors to Tf variance, with R2 of 0.58 (p<0.001); and for TwQmax, height and PA scores were the predictors, with R2 of 0.67 (p<0.001).
In the COPD patients, the results showed that FEV1%pred had the biggest effect on QMVC, except of gender difference, according to the values of standardized coefficients (β); R2 suggested that 6 independent variables including sex, FEV1%pred, MNI, SPD, TWEAK and myostatin were contributors of QMVC, together explaining 89% of QMVC variance. For endurance time, FEV1%pred and TNF-αwere contributors to Tf, explaining 25% of Tf variance. While for TwQmax, there was not any parameter correlated with it.
7.2 Pearson's correlation analysis for different methods of quadriceps functional tests
There was a significant correlation between TwQmax and QMVC in normal subjects (r=0.793, p=0.000), and a mild correlation between them in the COPD patients (r=0.396, p=0.001). The ratio of TwQmax/QMVC was 0.29 in normal subjects, and it was 0.32 in the COPD patients.
Quadriceps strength didn’t correlate with endurance time, in terms of either QMVC or TwQmax, in any of the groups.
Conclusions
1. For the healthy elderly age between 58-76yrs, the predicted normal values of the quadriceps functional tests should be as follows: QMVC(kg)=0.383+ 7.278×(sex) +1.967×PA score (score) +0.257×weight (kg) Tf(S)=2.143×MTMC(cm)+11.467×PAscore(score)+1.244×weight(kg)-34.759×(sex)-162.478 TwQmax (kg)=0.370×height (cm) + 0.898×PA score (score)-56.775
2. Quadriceps function commonly and substantially impaired in COPD patients compared with the healthy elderly, in terms of both strength and endurance capability, with strength impaired to a larger extent.
3. Airflow limitation, systemic inflammation, malnutrition and muscle atrophy are the main risk factors of SMD in COPD, with the former is the most significant one. Our study results support the notions that SMD is a complex related to multiple risk factors, with several mechanisms involved in it, and none of any one mechanism can fully explain SMD in COPD.
4. Systemic inflammatory cytokines including SPD, myostatin, TWEAK and TNF-αmight be potential candidate biomarkers for SMD in COPD.
5. As for the methodology, we conclude that each of the techniques has its own advantages and limitations. TwQmax has higher reproducibility, which is appropriate for repeated measurements in dynamic observation; while it presents with a higher inter-subject variability. In contrast, QMVC was shown to be lower in inter-subject variability, which offers a better measurement for subjects with full consciousness; whereas magnetic stimulation might be an ideal alternative technique for those who can not fully perform QMVC. With respect to endurance test, it was subject to the effort and cooperation of the subject and should not be used as choice of evaluation of quadriceps function in routine clinical practice.
目的:建立老年健康者外周骨骼肌(股四头肌)功能检测指标的正常值,调查稳定期COPD患者外周骨骼肌的功能状态,探索COPD患者SMD发生的相关机制;同时,比较三种不同的股四头肌功能检测方法的优缺点,为实践中选择检测方法提供依据。
材料与方法
一.研究对象:
研究对象包括稳定期COPD患者和年龄匹配的正常对照者。所有COPD患者(COPD组)均来自广州呼吸病研究所(国家重点实验室)门诊。COPD的诊断根据GOLD指南的标准,通过肺功能检查明确诊断。选择稳定期的患者,近两个月来无急性发作。通过详细询问病史、体检、心电图、胸片和血液生化检查等排除心血管疾患、风湿性疾病、神经肌肉疾病等伴发病。正常对照组受试者来自于广州医学院第一附属医院健康体检的同龄健康志愿者。
二.方法:
1.股四头肌力量评价和肌电记录方法:股四头肌功能测量技术按照Polkey等所述的方法,受试者坐在一张特制的椅子上,椅子的靠背可以活动,竖直或平放,受试者膝关节呈90度弯曲,悬垂于椅子末端。用一条无弹性皮带连接脚踝与应力测量器(测量范围0-150 kg)。皮带一端置于脚踝上1~2cm处,与脚踝垂直,另一端通过负荷感受器与应力测量器相连。每次测试前用标准力量定标。股四头肌体表肌电图(SEMG)的检测分别于股外侧肌肌腹、股直肌肌腹、股内侧肌腹表面安放测试电极,参考电极置于膝关节处。整个测试过程中必须确保受试者的膝关节角度不能改变,固定脚踝的皮带及力量负荷感受器应当始终与地板保持平行水平。然后进行下列检测
2.股四头肌功能检测的程序:股四头肌的功能检测项目共包括以下三项:磁刺激股神经诱发的股四头肌肌颤搐张力(TwQ)、股四头肌最大主动收缩力(QMVC)和耐力时间(Tf)。
2.1磁刺激诱发的肌颤搐张力(TwQ):方法参照Hamneg?rd等所述:将“8”字形的磁刺激条放置于股三角内股动脉外侧,同步记录TwQ及磁刺激范围内相应的复合肌肉动作电位(CMAP)。磁刺激股神经诱发股四头肌被动收缩的所产生的TwQ作为力量衡量指标、CMAP幅度作为肌电衡量指标。为了避免肌肉收缩后对TwQ的强化效应,首次磁刺激前受试者安静休息20分钟。首先以100%刺激强度时诱发的股四头肌颤搐张力(TwQ100%)最大处的部位定位并做好标记,以保证在整个磁刺激过程中的位置固定。然后分别用40%、60%、80%、90%和100%的刺激强度对受试者进行检测。
股四头肌被动收缩力的评估标准以最大肌颤搐张力(TwQmax)为准。TwQmax的判断标准为:随着磁刺激强度的逐步增加,所诱发的肌肉被动收缩力(即TwQ)及肌肉复合动作电位(即CMAP)出现平台。所有的131例受试者中,TwQ及CMAP均随着刺激量的增加而增加,其中的121例(对照组54例、COPD组67例)TWQ及CMAP最终出现平台,即检测到TwQmax。对于能检测到TwQmax的121例受试者,以三次_(100%)磁刺激强度下所诱发的TwQ(即TwQ_(100%))的平均值作为最终TwQmax的结果。有10例,包括对照组6例(男性2例,女性4例)、COPD患者组4例(均为男性)未检测到TwQmax,即随着刺激强度的增加,没有观察到TwQ或CMAP平台的出现。此10例受试者中的9例体重指数明显高于其他受试者(24.5~31 kg/m~2), TwQ_(100%):QMVC的比值均<0.16;另外一例其体重指数正常,但TwQ_(100%)的最大值(25kg左右)明显高于其他所有受试者,TwQ_(100%):QMVC的最高比值为0.58,每次诱发的TwQ_(100%)值不稳定、变异度大(变异率大于20%)。因此,此10例受试者未纳入TwQmax的统计分析。
2.2股四头肌最大主动收缩力(QMVC)的测试:受试者端坐体位,膝关节与髋关节同时呈900,尽最大力量向前伸腿产生的力量即QMVC。通过电脑屏幕的同步显示,受试者可以观察自身的力量曲线,同时鼓励受试者,使其每次尽最大力量,直到QMVC达到平台,没有再增加趋势。每次QMVC持续3-5秒,中间间隔大约45-65秒,防止肌肉疲劳,具体间隔时间结合个体受试者的自觉症状及要求进行调整。重复检测至少有连续三次QMVC重复性较好(各数值之间差异性<10%),这三次中的最大数值即被认为QMVC。
2.3耐力测试:耐力是指在60%的QMVC时等长收缩所持续的时间(秒)。目标力量设置用每个受试者自身QMVC的55%~65%,在电脑屏幕上显示。受试者持续用力,使力量曲线维持在上述范围。当力量低于50%的QMVC时,允许小于3秒钟的放松,然后再努力维持力量曲线在上述范围。在持续用力过程中如果力量下降低于50%的QMVC时间大于3秒,则视为耐力测试结束。最后结果采用总的用力持续时间之和,即达到疲劳所需要的总时间为耐力时间(Tf)。
2.4数据采集和分析:表面电极和应力测量器的信号与放大器连接,然后在数据采集系统(PowerLab 8/16SP)的支持下以2 Khz(磁刺激时采样频率为10Khz)的采样频率同步记录并保存于苹果电脑中,待后以Chart 5.2软件分析。表面肌电信号以计算均方根(RMS-100ms)用来衡量肌电幅度,计算M波的正负峰值差以衡量CMAP幅度。
3.营养指标的评估:采用多参数营养不良评分表(MNI)对患者的营养状况进行总体评价。此评估主要由血液生化指标和人体测量学指标组成。前者包括血清白蛋白(ALB)、转铁蛋白(TFR)、甘油三脂(TRG)及胆固醇(CHO);后者包括身高、体重、肱三头肌皮下脂肪厚度(TSF)、上臂中点周径(MAC)、上臂中点肌肉周径(MAMC)、腹围等。根据身高体重计算受试者的体重指数(BMI)及标准体重(IBM)。
4.股部肌肉体积的估算:采用间接指标。以股部中点周径及皮下脂肪的测量值,根据公式推算出股部中点的肌肉周径(MTMC)。
5.肺功能测试:所有的受试者均进行常规肺功能测试,测试项目包括FEV1、FVC、FEV1/FVC(%)、PEF等肺功能指标。COPD患者的肺功能指标需要观察吸入支气管舒张剂前后的对比,在排除合并哮喘后,则选取支气管舒张剂吸入后的数值。
6.日常活动评分:日常活动(PA)评分参照Serres等评分方法,对受试者进行问卷调查,共涉及5大项目:职业、日常活动、体育运动、业余爱好、以及除外睡眠和运动以外的业余时间活动,具体共由19项组成,每一项按强度及频度分级,最后算出总分。
7.血液中炎症因子的检测:共检测8种细胞因子和炎症介质。用酶联免疫分析(ELISA)法检测以下7种细胞因子:肌抑制素、肿瘤坏死因子(TNF)-α、TNF样凋亡诱导因子(TWEAK)、表面活性蛋白D(SPD)、C反应蛋白(CRP)、白介素(IL)-1β及IL-6。用细胞免疫化学(ICC)法检测核因子KppaB(NF-κB)的表达:分别检测外周血液中单核细胞及中性粒细胞中核因子NF-κB的表达,以半定量方法对ICC检测结果进行分析,取两种细胞对NF-κB表达的平均值作为最后结果。
三.研究流程
开始测试时间为清晨(7:30-8:30分),受试者空腹,留取静脉血标本6ml, 2ml不加抗凝剂,用以检测血清蛋白及血脂;4ml抗凝血离心后用以检测血浆中及血细胞内的细胞因子的表达。血标本暂时保存于4℃冰箱,4小时内进行初步处理,待后进一步处理。人体学测量亦在空腹进行。早餐后进行股四头肌功能测试,首先进行磁刺激检测,然后依次进行QMVC测试及耐力测试,每项功能测试前受试者分别安静休息20分钟。最后(或当日下午)进行肺功能测试及日常活动评分问卷调查。
四.统计学处理和结果分析
应用SPSS10.0统计软件分析。计量资料以±s表示,分类变量以百分比(%)表示,以P<0.05为差异有统计学意义。COPD组与对照组之间比较采用非配对t检验及卡方检验。主客观测试方法变异度的比较采用两种方法:(1)个体间变异度的比较,以变异系数进行评估,变异系数[CV=(标准差/均数)×100%];(2)重复测量数据变异度的比较,分别以三次重复测量数据之间的变异率进行评估,变异率=[(最大值-最小值)/(最大值+最小值)×100%]。两组内的股四头肌功能检测的三项指标与其相关因素之间均采用逐步回归分析法;股四头肌功能检测指标的收缩力和耐力之间,以及主动与被动两种收缩力之间均采用简单线性相关分析。
结果
1.一般状况:正常对照组60例,其中男性21例,女性39例;COPD组71例,其中男性54例,女性17例,性别比例存在差异性(P<0.01)。两组受试者的平均年龄分别为:正常对照组(63.98±5.77)岁,COPD患者组(65.17±6.80)岁,组间比较无差异性(P=2.29)。两组受试者身高的平均值分别为:正常对照组(161.03±7.80)cm、COPD患者组(162.22±7.14)cm,组间比较无差异性(P=0.36)。所有受试者均未参加过任何康复或体能训练,未曾接受营养支持治疗。
2.肺功能测试结果:正常对照组每一位受试者肺通气功能测试的各项指标均在正常范围内,其中第一秒用力呼气容积占预计值百分比(FEV1%pred)为(97.10±8.90)%,而COPD患者的FEV1%pred为(37.76±14.93)%,两组间比较有显著差异性(P<0.001)。根据Gold分级标准,本研究中58%的COPD患者肺功能下降的严重程度属于中重度。
3.营养指标评分:多参数营养不良评分(即MNI)结果显示:COPD组患者的MNI为(7.75±3.86)分,正常对照组的MNI为(1.13±0.96)分,两组间比较有显著差异性(P<0.001),显示出COPD患者的营养状况普遍下降。
4.肌肉体积评估:正常对照组MTMC的平均值为(43.19±3.55)cm,COPD患者组其平均值为(37.77±3.73)cm,两组间比较有显著差异(P<0.001),显示出COPD组患者的股部肌肉体积明显下降。
5.日常活动评分:正常对照组的PA评分的平均值为(7.97±1.21)分,COPD患者组PA评分的平均值为(5.25±1.38)分,两组间比较有显著差异性(P<0.001),显示出COPD组患者的日常活动明显减少。
6.肌肉功能测试结果及方法学对比:
6.1肌肉功能测试结果
6.1.1检测结果:正常对照组男性的QMVC为(42.06±7.61)kg、耐力时间为(81.09±22.58)秒、TwQmax为(13.91±3.94)kg,而COPD患者组男性的QMVC为(23.26±5.74)kg、耐力时间为(51.13±18.73)秒、TwQmax为(7.25±2.29)kg;女性正常对照组的QMVC为(29.24±4.58)kg、耐力时间为(83.44±23.64)秒, TwQmax为(7.75±1.75)kg,而女性COPD组的QMVC为(15.55±4.25)kg、耐力时间为(56.31±15.49)秒,TwQmax为(4.18±0.89)kg;各组间比较均有显著差异性(P<0.001)。
以正常对照组受试者肌肉功能三项检测指标的检测值为因变量,以相关因素作为自变量,计算出正常健康老龄者(58-76岁)的股四头肌功能指标回归方程(正常值预计方程)如下: QMVC (kg)=0.383+ 7.278×性别+1.967×PA评分(分) +0.257×体重(kg) Tf (秒)=2.143×MTMC(cm)+11.467×PA评分(分)+1.244×体重(kg)-34.759×性别-162.478 TwQmax (kg)=0.370×身高(cm) + 0.898×PA评分(分)-56.775
6.1.2股四头肌功能下降的发生率
以对照组受试者肌肉功能检测值的95%可信区间的下限为标准判断,94%的患者存在主动收缩功能(即QMVC)下降;78%的患者存在耐力功能(即Tf)下降;90%的患者存在被动收缩功能(即TwQmax)下降。所有COPD患者中,任何一项出现异常的发生率为94%,同时存在QMVC、Tf及TwQmax三项指标均下降的发生率为59%。
根据股四头肌功能正常值预计方程95%可信区间的下限为标准判断,95%的患者存在QMVC下降;45%的患者存在Tf下降;85%的患者存在TwQmax下降。所有COPD患者中,任何一项出现异常的发生率为95%,同时存在QMVC、Tf及TwQmax三项指标下降的发生率为46%。
6.1.3股四头肌功能下降的严重程度
以正常对照组肌肉功能检测的实测值为基准,男女分层比较显示:男性COPD患者的QMVC平均下降45%、耐力时间(即Tf)平均下降37%,TwQmax平均下降47%;女性COPD患者的QMVC平均下降48%、Tf平均下降33%、TwQmax平均下降44%。
根据健康老龄者股四头肌功能正常值的预计方程,COPD患者的QMVC平均占正常预计值的65%、Tf平均占正常预计值的73%,TwQmax平均占正常预计值的67%。
6.1.4肌肉功能下降的特点:就三项测试指标在COPD患者中下降的严重程度进行对比,结果显示:主动收缩力(即QMVC)平均下降46%、被动收缩力(即TwQmax)平均下降45%、耐力时间(即Tf)平均下降为35%。总体评价:收缩力下降程度较耐力下降的严重程度更显著。
6.2主客观测试方法变异度的比较
6.2.1重复测量数据变异度的比较
对于主客观测试方法重复性的评估,以三次重复测量数据变异率进行对比。组内男女分层比较,TwQmax和QMVC的变异率分别为:正常对照组(男性2.3 v 3.3%;女性3.4% v 3.7%);COPD患者组(男性3.9% v 8.5%;女性3.3% v 5.1%),显示TwQmax的变异率低于QMVC,即前者的重复性高于后者;但所有的变异率均<10%。
6.2.2个体间变异度的比较
对于个体间变异度的比较,以变异系数衡量。剔除未达到最大刺激强度的受试者,就TwQmax及QMVC进行对比,二者的变异系数分别为:正常对照组(男性27% v18%;女性23%v15%);COPD患者组(男性32% v 24%;女性21% v 27%)。组内男女分层分析结果显示:对照组的男性及女性、COPD患者组的男性,此三组中TwQmax的变异系数均高于和QMVC,即TwQmax在个体间的变异度高于QMVC;仅在COPD女性中,TwQmax在个体间的变异度低于QMVC。此结果显示出TwQmax在个体间变异度普遍高于QMVC。
7.细胞因子
细胞因子检测结果分别为:SPD(ng/ml):正常组(31.97±5.54)、COPD组( 47.52±17.26 ) ; Tweak (pg/ml) :正常组( 447.57±84.25 )、COPD组(583.39±241.50);肌抑制素(ug/ml):正常组(31.76±9.39)、COPD组(48.71±21.01);TNF-α(pg/ml):正常组(6.23±4.49)、COPD组(13.91±2.86),以上4种细胞因子在COPD组与正常对照组之间比较,均有显著差异性(各P<0.001)。另外4种包括IL-6、IL-1β、CRP及NF-κB也在COPD组有升高趋势,但统计分析与正常对照组之间无显著差异(各P>0.05)。细胞因子筛查结果显示:所有检测的8项细胞因子均在COPD组升高,但其中仅有4种达到统计学意义。
8.相关分析
8.1逐步回归分析
正常对照组的QMVC与性别、PA评分、体重显著相关(R~2 =0.61,p<0.001);耐力时间与PA评分、MTMC、体重及性别相关(R~2 =0.58,p<0.001);TwQmax与身高及PA评分相关(R~2 =0.67,p<0.001)。
COPD患者组QMVC的实测值与性别(0.513)、肺功能FEV1%pred(0.240)、肌抑制素(-0.231)、SPD(-0.149)、MN(I-0.168)及TWEAK(-0.192)相关(R2=0.89,p<0.001);耐力时间与FEV1%pred(0.421)及TNF-α(-0.289)相关(R2=0.25,p<0.001);而TwQmax与以上各因素均无相关性。逐步回归方程的β系数显示:FEV1%pred在COPD患者的QMVC指标中为仅次于性别因素的相关因子;在耐力测试指标中FEV1%pred的β值也高于TNF-α。
8.2不同的股四头肌功能评估方法之间的线性相关分析
收缩力与耐力之间:正常对照组及COPD患者组的两种收缩力与耐力指标之间均无相关性。就主动收缩力(即QMVC)与Tf之间的相关系数为例,其在正常对照组为r=0.106(p=0.421)、在COPD患者组为r=0.225(p=0.06)。
被动与主动两种收缩力之间:剔除没有达到TwQmax的受试者,分析TwQmax与QMVC之间的相关性,结果显示:在54例正常受试者中二者显著正相关(r=0.793, p=0.000),在67例COPD患者中二者也呈正相关(r=0.396, p=0.001);TwQmax与QMVC之间的比值在正常对照组为0.29、在COPD患者组为0.32。
结论
1.正常老年(58-76岁)健康者股四头肌功能检测指标的预测公式为: QMVC (kg)=0.383+ 7.278×性别+1.967×PA评分(分) +0.257×体重(kg) Tf (秒)=2.143×MTMC(cm)+11.467×PA评分(分)+1.244×体重(kg)-34.759×性别-162.478 TwQmax (kg)=0.370×身高(cm) + 0.898×PA评分(分)-56.775
2.与同龄健康者相比,94%的COPD患者存在不同程度的股四头肌功能下降,半数以上患者的肌肉功能严重下降;其中,收缩功能较耐力功能下降的程度更为显著。
3.COPD的气流阻塞程度、全身慢性炎症反应、营养不良、肌肉萎缩等均是导致SMD发生的主要危险因素,其中,气流阻塞与SMD的发生关系最密切。支持COPD患者SMD的发生与多种因素有关的观点。
4.慢性系统性炎症反应作为COPD患者SMD发生的主要危险因素之一,其中的细胞因子SPD、肌抑制素、Tweak及TNF-α在COPD中显著性升高,是COPD发生SMD的候选生物标记物和干预切入点。
5.股四头肌功能检测的三种方法各有其优缺点。TwQmax虽然无需受试者的主观配合,可用于无法主动配合的受试者,重复性好,有利于动态监测;但其在个体间变异性较大,不利于群体之间的比较。QMVC检测方法较简单,个体间变异度小,可以较准确地反映肌肉的收缩功能;但需要受试者配合,重复检测的变异率稍大于磁刺激诱发的TwQmax。耐力评估方法较复杂、持续时间长,对受试者主客观配合的要求高,不适宜作为常规检测。
Background Chronic obstructive pulmonary disease (COPD) is a multiple component disorder with systemic effects. Skeletal muscle dysfunction (SMD) is one of the most important systemic manifestations of COPD. SMD has been recognized as a contributing factor related to reduced exercise capacity, impaired quality of life, and increased mortality and health care utilization. There is increasing concerns on the potential role of peripheral muscles dysfunction in COPD as it might be a potential site of intervention for improving patient’s functional status. A variety of mechanisms related to SMD in COPD have been postulated, such as systemic inflammation, malnutrition, muscle disuse and atrophy, etc; while none of the above mentioned mechanisms could fully explain SMD in COPD. Quadriceps function assessment was used in majority of the studies for assessment of peripheral skeletal muscle function as it is readily accessible and is a primary locomotor muscle. Accurate assessment of skeletal muscles function is important for investigation of the mechanism of SMD in COPD. Comprehensive evaluation of muscles function should include the assessment of both of strength and of endurance capabilities. The conventional test for assessment of quadriceps strength is the maximal volitional contraction (QMVC), which is depending on subjects’volitional effort and affected by learning effects. In the past twenty years, magnetic stimulation of femoral nerve has been employed to assess quadriceps strength non-volitionally, which is not influenced by subjects’effort and co-operation. Furthermore, proper evaluation of the prevalence and severity of SMD in COPD relies also on the proper control data from the age-matched normal subject. So, adequate normal values of quadriceps function in age-matched healthy elderly were important for the study.
Objective The purposes of the study are to establish normal predicted values for quadriceps muscle function tests in healthy elderly, which can provide proper control data for age-matched COPD patients, to evaluate the prevalence and severity of SMD in patients with COPD, and to explore the related risk factors. Meanwhile, the methods of quadriceps function testing were compared in order to provide evidence for selection of testing for clinical evaluation.
Materials and Methods
1. Study subjects
Seventy-one patients with stable COPD and 60 age-matched healthy volunteers were recruited for the study. Patients were recruited from outpatients’clinics of Guangzhou Institute of Respiratory Disease (State Key Lab of Respiratory Disease) during the period from Mar 2007 to Oct 2007. The diagnosis of COPD was according to the criteria recommended by the GOLD guideline. Significant co-morbidities were excluded by medical history, physical check-up and conventional lab investigations. Subjects exclusion criteria included history of exacerbation in the preceding month, co-morbidities of cardiac, rheumatologic or neuromuscular disorders or unwilling to participate in the study. Subjects in control group were recruited from health check-up department of First Affiliated Hospital of Guangzhou Medical College.
2. Quadriceps function assessment
Quadriceps function test was performed with the technique described by Polkey et al, with a specially designed chair from which the back was removed and laid flat. The test was performed with the subject’knee flexed at 90 degree over the end of the chair. The ankle of the dominant leg was placed in an inextensible strap that was connected to a strain gauge, and the strain gauge was calibrated after each test with weights of known amounts. The force output and compound muscle action potential (CMAP) of surface electromyography (SEMG) was recorded simultaneously. SEMG was recorded for quadriceps muscles of rectus femoris, vastus lateralis and vastus medialis. Quadriceps muscle functional test included the three items: twitch tension (TwQ) evoked by magnetic stimulation of the femoral nerve, strength of maximal volitional contraction (QMVC), and endurance time.
2.1 TwQ
TwQ was induced by magnetic stimulation of the femoral nerve. Subjects were studied supine on the apparatus, with knee joints flexed at 90 degree over the end of the apparatus. Femoral nerve stimulation was performed using a 70-mm figure-of-eight coil powered by a Magstim 200 stimulator. The coil head was positioned high in the femoral triangle just lateral to the femoral artery. Minor positional adjustments were made to the coil whilst simultaneously monitoring quadriceps force during stimulation to determine the optimum position. TwQ evoked by stimulation at 100% intensity of the stimulator power output (TwQ_(100%)) was used to determine the best spot. The best spot that resulted in the largest TwQ_(100%) was identified and marked in order that the same position was used throughout the range of stimulator outputs. To avoid twitch potentiation, there was a rest period of 20 minutes before the start of the magnetic stimulation. After identifying the best location, stimulations of varying intensities were administered at a stepwise increment in the stimulator’s output. For each subject, stimulation was administrated at 40%, 60%, 80%, 90% and 100% intensity of the stimulator power output, respectively.
Quadriceps non-volitional strength was assessed with the maximal TwQ (TwQmax). To determine whether TwQ reached to the TwQmax, a near plateau in TwQ and CMAP with increasing power output were observed, indicating maximal depolarization of the femoral nerve. In the present study, TwQmax was achieved in 121 subjects (54 normal subjects and 67 patients), and the result of TwQmax was finally determined as the mean of three reproducible TwQ_(100%) for these subjects. TwQmax was not achievable in 10 participants (6 normal subjects and 4 patients), as a plateau in either TwQ or CMAP amplitude was not reached with the increasing intensity of the stimulator power output up to 100%. Compared with the 121 subjects mentioned above, 9 of the 10 participants had higher BMI (24.5~31 kg/m~2) and a lower ratio of TwQ100%:QMVC (<0.16); the remain one subject had a normal BMI but presented a much higher TwQ100% (25kg), with a higher variability of TwQ100%(>20%). Therefore, the data from the 121 subjects was used for TWQmax in statistical analysis, excluding the data from the 10 subjects.
2.2 QMVC
QMVC was measured as the subject in an upright position, with hip and knee joints at 90 degree of flexion. Subjects were required to try to extend their dominant leg as hard as possible against the inextensible strap mentioned above. A computer screen was in front of the subjects for the force generated was visible to subject and investigator; so the computer screen was served as a positive feedback mechanism to help subjects to perform the test. Repeated efforts were made with vigorous encouragement until there was no improvement in performance. Efforts were sustained for about 3~5 seconds and rested for about 45~65 seconds between each contraction in an effort to avoiding fatigue. If maximal values were reproducible (<10% variability) for consecutive three times, i.e., the generated strength reached a plateau, the highest value of these three contractions was considered as the QMVC.
2.3 Endurance time
Endurance of the quadriceps was evaluated during an isometric contraction. After 10 minutes of rest following the QMVC maneuvers, subjects were instructed to maintain a tension corresponding to 55%~65% of their own QMVC until exhaustion. The feedback mechanism served by the computer screen helped subjects to maintain the determined submaximal tension. Subjects were strongly encouraged to pursue until tension dropped to 50% QMVC or less for more than 3 seconds (S). Thus, quadriceps endurance was defined as the time to fatigue (Tf), and the time at which the isometric contraction at 60% of maximal voluntary capacity could no longer be sustained.
2.4 Data acquisition
The signal was amplified 1 KHz and passed to PowerLab 8/16 SP hardware and a computer running Chart 5.2 software. SEMG signal from quadriceps was sampled at 2 kHz when QMVC and enduring tests were performed; and it was sampled at 10 KHz when magnetic stimulation of femoral nerve was administered. The amplitude of SEMG in QMVC was determined by calculating the root mean square (RMS-100 ms time constant) over the same contraction period for each muscle. Amplitudes of CMAP were determined by calculating the difference between the peak and the minimum of M-wave amplitudes when TwQ was elicited.
3. Nutritional status assessment
Subject’s nutritional status was evaluated by using a multiparameter nutritional index (MNI), which consisted of anthropometric measurements and visceral proteins level. Anthropometric measurements included body weight, triceps skinfold thickness (TSF), mid-arm muscle circumference (MAMC). Albumin and transferrin plasma concentration was used as visceral proteins store. In addition, serum triglyceride and cholesterol levels were also determined.
4. Quadriceps muscle mass evaluation
Quadriceps muscle mass was evaluated indirectly with midthigh muscle circumference (MTMC), which calculated by mid-thigh skinfold thickness and circumference. MTMC was considered different from other anthropometric indices because midthigh muscles mainly consist of quadriceps, which was the muscle we aimed to study.
5. Spirometric function
Spirometric function was tested in all of the participants. For the patients with COPD, it was required the confirmation of irreversible airflow limitation with post-bronchodilator FEV_1/FVC<70%.
6. Level of daily physical activity
Level of daily life physical activity (PA) was evaluated by using a PA questionnaire adapted for the elderly in China. The original questionnaire on habitual PA consisted of 19 items, scored the past 3 year's household activities, sports activities, and other physically active leisure-time activities and gave an overall PA score. The subjects were asked to describe type of the PA, hours per week spent on it, and period of the year in which the PA was normally performed.
7. Cytokines
Eight cytokines were screened in the present study. Antibody sandwich enzyme-linked immunosorbent assay (ELISA) was used to analyze the level of cytokines in plasma, and immunocytochemistry (ICC) was employed to detect the expression of nuclear factor KppaB (NF-κB) in peripheral blood lymphocytes and neutrocytes.
The concentration of seven cytokines in plasma was determined in duplicate by using ELISA kits. These cytokines included surfactant protein D (SPD), myostatin, tumor necrosis factor (TNF-α), interlukin (IL)-6, IL-1β, TNF-like weak inducer of apoptosis (TWEAK) and C reactive protein (CRP). The expression of NF-κB in peripheral blood lymphocytes and neutrocytes was detected by using immuno-chemistic kits. Semi-quantitative methods were employed to analyze the results of the ICC.
7. Study Procedure
Most of the experiments were performed in the morning. Blood sample collection and anthropometric measurements required subjects to present with an empty stomach. After breakfast, skeletal muscle performance was assessed. Quadriceps function was tested as TwQ was performed firstly, with QMVC and endurance capabilities followed in order. Before each of the items of the functional test, subjects were asked to rest quietly for 20 minutes. At the end of the morning or in the afternoon of the day, spirometric variables were measured, and finally, subjects were asked to respond to the questionnaire of physical activities.
8. Statistical analyses Statistical analysis was performed using SPSS 10.0 statistical package for windows. Measurement data were summarized by mean±SD, and categorical data were summarized by number (percentage). P value <0.05 was considered statistically significant. Two independent-sample t-tests and Chi-Square test were used for univariate testing between the COPD patients and the controls. The variability for both QMVC and TwQmax were investigated by using the following two methods: (1) Intersubject variability, which was determined by calculating the coefficient of variation [CV=(SD/mean)×100%]; (2) Reproducibility of the measurements, which was determined by calculating the variation rate in the repeated measurement data from 3 times, and the variation rate=[(maximum-minimum)/(maximum+minimum)]×100%. In both controls and patients groups, multiple regression models were developed by stepwise method to determine the independent factors respectively contributing to the 3 items of quadriceps performance, i.e., TwQmax, QMVC and endurance. Pearson's correlation analysis was employed to determine the relationship between the variables of strength and endurance time, and between the volitional and non-volitional contraction.
Results
1. Characteristics of the subjects
There were 60 normal subjects in control group, with 21 male and 39 female, and there were 71 patients in COPD group, with 54 male and 17 female; significant difference was observed in gender constituent ratio between the two groups, with P<0.01.
The mean age was (63.98±5.77) years in controls and (65.17±6.80) years in the patients (P=2.29); and the mean height was (161.03±7.80) cm in controls and (162.22±7.14) cm in the patients, respectively, with P=0.36. The results showed that the patients and controls were matched, with respect to age and height. No subjects were receiving nutritional support therapy or had participated in any rehabilitation program previously.
2. Pulmonary function
Spiro metric function test showed that, the mean forced expiratory volume for 1 S (FEV1) was (97.10±8.90) %pred in normal subjects, while it was (37.76±14.93) %pred in COPD patients, and there was significant difference between the two groups (P<0.001). The results showed that patients with COPD had, on average, severe airflow limitation as defined by the GOLD criteria.
3. Nutritional status
Multiparameter nutritional index (MNI) was (7.75±3.86) score in the COPD patients and (1.13±0.96) score in normal subjects, with significant difference between the two groups (P<0.001).The results showed that malnutrition was commonly existed in the patients with COPD.
4. Quadriceps muscle mass
MTMC was (37.77±3.73) cm in the COPD patients and (43.19±3.55) cm in normal subjects, with P<0.001, showing that the patients had decreased muscle mass compared with normal subjects.
5. Level of daily physical activity
PA score was (5.25±1.38) score and (7.97±1.21) score, in the COPD patients and normal subjects, respectively, with significant difference existing between the two groups (P<0.001). The PA questionnaire showed that the patients with COPD had less physical activities in their daily lives compared with the normal subjects.
6 Quadriceps function assessment and methodological issues 6.1 Quadriceps function assessment
When analyzing the results in subgroups of men and women, QMVC was [(23.26±5.74) kg v (42.06±7.61) kg for male, and (15.55±4.25) kg v (29.24±4.58) kg for female]; endurance time was [(51.13±18.73) S v (81.09±22.58) S for male, and (56.31±15.49) S v (83.44±23.64) S for female]; TwQmax was [(7.25±2.29) kg v (13.91±3.90) kg for male, and (4.18±0.89) kg v (7.76±1.75) kg for female] in the patients and in controls, respectively, with each of P<0.001.
6.1.1 Predicted equation for normal values
For the healthy elderly (58~76 years old), the normal values of the quadriceps functional tests were defined as the dependent variant, and the candidate factors related to quadriceps function were analyzed as the independent variant by the stepwise regression correlation models. Consequently, the predicted normal values were given as the following 3 equations: QMVC(kg)=0.383+ 7.278×(sex) +1.967×PA score (score) +0.257×weight (kg) Tf(S)=2.143×MTMC(cm)+11.467×PAscore(score)+1.244×weight(kg)-34.759×(sex)-162.478 TwQmax (kg)=0.370×height (cm) + 0.898×PAscore (score)-56.775
6.1.2 Prevalence of quadriceps dysfunction
According to the lower limit of the 95% confidential interval of the data from the normal subjects, QMVC was impaired in 94% of the COPD patients; Tf was impaired in 78% of the COPD patients, and TwQmax was impaired in 90% of the patients. There were, 94% of the patients with quadriceps dysfunction, in terms of any item of the three indices, and 59% of them with quadriceps dysfunction, in terms of all the 3 items including QMVC, Tf and TwQmax.
According to the lower limit of 95% confidential interval of the predicted normal values showed above, QMVC was impaired in 95% of the patients, Tf was decreased in 45% of them, and TwQmax was impaired in 85% of them. There were, 95% of the patients with quadriceps dysfunction, in terms of any item of the three indices, and 46% of them with all the 3 items including QMVC, Tf and TwQmax.
6.1.3 Severity of quadriceps dysfunction
QMVC was decreased by 45%, Tf by 37%, and TwQmax by 47%, respectively, in male patients, compared with normal male subjects; QMVC, Tf and TwQmax were decreased by 48%, 33% and 44%, respectively, in the female patients, compared with the female controls.
According to the prediction equation for normal values showed above, QMVC was only 65%, Tf was 73%, and TwQmax was 67% of predicted values, respectively, in the COPD patients.
6.1.4 Characteristic of quadriceps dysfunction
With respect to extent of the quadriceps dysfunction, QMVC, Tf and TwQmax were decreased by 46%, 35% and 45%, respectively, compared with normal subjects. Overall, strength showed a larger extent than endurance time in the impairment of the quadriceps functional tests.
In total, quadriceps function was commonly and substantially impaired in the COPD patients, compared with the age-matched normal subjects.
6.2 Variability of volitional and non-volitional techniques
6.2.1 Reproducibility of repeated measurements
Reproducibility of the measurements was assessed by calculating the variation rate of the repeated measurement data from 3 testings. The variation rates of TwQmax and QMVC were [2.3% v 3.3% for male, 3.4% v 3.7% for female] in normal subjects, and [3.9% v 8.5% for male; 3.3% v 5.1% for female] in COPD patients, respectively. According to the results, TwQmax presented a higher reproducibility than QMVC in all of the subjects. However, the variation rates for both TwQmax and QMVC were less than 10% in all of the groups.
6.2.2 Inter-subject variability
Inter-subject variability was assessed with the coefficient of variation (CV). When analyzing subgroups of women or men, CV of TwQmax and QMVC was [28% v 18% for male; 23% v15% for female] in normal subjects, and [32% v 24% for male; 21% v 27% for female] in COPD patients, respectively. The result showed that TwQmax demonstrated greater variability than QMVC in all of the groups except of the female patients group, in which variability was lower for TwQmax than it for OMVC, according to the CV.
7. Cytokines
Concentrations of the 4 cytokines in plasma were elevated in COPD patients as compared with control subjects. The results were showed as following: SPD (ng/ml): (31.97±5.54) vs (47.52±17.26); Tweak (pg/ml): (447.57±84.25) vs (583.39±241.50); myostatin (ug/ml): (31.76±9.39) vs (48.71±21.01); TNF-α(pg/ml): (6.23±4.49) vs (13.91±2.86) (all p<0.05). Another 4 cytokines including IL-6, IL-1β, CRP, and NF-κB were also showed the tendency of elevation in COPD patients comparing with control subjects, but no statistical significance was observed (all p<0.05).
7. Correlations
7.1 Multivariate stepwise regression analysis
In normal control subjects, stepwise regression analysis showed that QMVC could be predicted by sex, PA scores and weight, with R2 of 0.61 (p<0.001); for endurance time, PA scores, MTMC, weight and sex were the predictors to Tf variance, with R2 of 0.58 (p<0.001); and for TwQmax, height and PA scores were the predictors, with R2 of 0.67 (p<0.001).
In the COPD patients, the results showed that FEV1%pred had the biggest effect on QMVC, except of gender difference, according to the values of standardized coefficients (β); R2 suggested that 6 independent variables including sex, FEV1%pred, MNI, SPD, TWEAK and myostatin were contributors of QMVC, together explaining 89% of QMVC variance. For endurance time, FEV1%pred and TNF-αwere contributors to Tf, explaining 25% of Tf variance. While for TwQmax, there was not any parameter correlated with it.
7.2 Pearson's correlation analysis for different methods of quadriceps functional tests
There was a significant correlation between TwQmax and QMVC in normal subjects (r=0.793, p=0.000), and a mild correlation between them in the COPD patients (r=0.396, p=0.001). The ratio of TwQmax/QMVC was 0.29 in normal subjects, and it was 0.32 in the COPD patients.
Quadriceps strength didn’t correlate with endurance time, in terms of either QMVC or TwQmax, in any of the groups.
Conclusions
1. For the healthy elderly age between 58-76yrs, the predicted normal values of the quadriceps functional tests should be as follows: QMVC(kg)=0.383+ 7.278×(sex) +1.967×PA score (score) +0.257×weight (kg) Tf(S)=2.143×MTMC(cm)+11.467×PAscore(score)+1.244×weight(kg)-34.759×(sex)-162.478 TwQmax (kg)=0.370×height (cm) + 0.898×PA score (score)-56.775
2. Quadriceps function commonly and substantially impaired in COPD patients compared with the healthy elderly, in terms of both strength and endurance capability, with strength impaired to a larger extent.
3. Airflow limitation, systemic inflammation, malnutrition and muscle atrophy are the main risk factors of SMD in COPD, with the former is the most significant one. Our study results support the notions that SMD is a complex related to multiple risk factors, with several mechanisms involved in it, and none of any one mechanism can fully explain SMD in COPD.
4. Systemic inflammatory cytokines including SPD, myostatin, TWEAK and TNF-αmight be potential candidate biomarkers for SMD in COPD.
5. As for the methodology, we conclude that each of the techniques has its own advantages and limitations. TwQmax has higher reproducibility, which is appropriate for repeated measurements in dynamic observation; while it presents with a higher inter-subject variability. In contrast, QMVC was shown to be lower in inter-subject variability, which offers a better measurement for subjects with full consciousness; whereas magnetic stimulation might be an ideal alternative technique for those who can not fully perform QMVC. With respect to endurance test, it was subject to the effort and cooperation of the subject and should not be used as choice of evaluation of quadriceps function in routine clinical practice.
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