Differing Effects of Airway Obstruction on Physical Work Capacity and Ventilation in Men and Women With COPD

Differing Effects of Airway Obstruction on Physical Work Capacity and Ventilation in Men and Women With COPD* Rick Cart er, PhD , FCCP; Brooke Nicotra, MD , FCCP; and Gary Hub er, MD Background: Although th e natural hi story of COPO is thought to be well known, studies assessin g differen ces in the onset and course of the di sea se by gender ar e surprisingly lacking. This study is a cross-secti onal analysis using progressive cycle ergome try exercise testing to assess male and female patients at specifi c levels of airway obstruction to see if they differ in th eir exercise capacity and decline in functional capacity. Methods: The study group included 417 patients with COPO, 55 to 85 years of age, who wer e compared with 29 controls of similar age; all patient s had COPO (FEVdFVC<75% predicted) without restrictive di sease. Exercise testing in groups ba sed on th e level of pulmonary dysfunction defin ed by FE Vt/FVC ratios (mild , 60.5 to 69.5%; moderate , 50.5 to 60.5% ; severe <50.5%) wa s analyzed. Data were evalua te d usin g th e Statistical Anal ysis System, analyzing gender and degree of airway obstruction and adjusting for any difference in age and peak exercise heart rate (covariate analysis of variance). Results: Men demonstr at ed progressive reductions of bod y weight, exercise ability (assessed by th e Voz), oxygen puls e (OzP, an indicator of stroke volume), and maximum exercise ventilation (VEma x) eve n with mild pulmonary dysfunction. Women did not lose weight , and maintained usual exercise ability (Vo z, VEmax) and OzP until moderate or severe disease was present. Additional confirmation of a decrease in cardiac function for men with mild airway obstruction (p
wom en presented with COPO at lower levels of tobacco smok e exposure than men for th e enti re group (43.8 vs 63.0 pack-years, p
The natural histor y of ch ro nic obs tructive p ulm onary di sease (COPD) has been ex te nsive ly revie wed .' There is a vas t a mo un t of d at a that esta blish ed normal predict ed pulmonary function va lues by gender and ra ce , ye t there is a relative absence of data assessin g gender differences in th e onse t, course , and impact of COPD . Because of th e lack of data relating gender differences to a d eclin e in lung

fun ct ion and the assoc ia te d changes m anifest ed in physical wo rk performa nce , th e true co nse q ue nces of this chronic di sease pro cess have not been a p p reciat ed . Gender differen ces in m en and wo men d o ex ist fo r some lung di seas es. Male tobacco smoke rs, for exa m pl e , ofte n d ev elop sq ua m ous cell lung ca rci no mas, but female sm oke rs present with inc reased numbers of adenocarcinomas.V' Whether this differen ce is attributable to ge n de r or to a no ther va ri ab le is unclear , as is th e m ech anism . Further , wit hi n th e population with COPD, di fferen ces in m ortality ex ist bet ween m en and women , wit h nearly a threefold excess m ortality for m en (28 a nd 10 d eaths per 100 ,000 , respectivelyl.f Based on th e b est avail able

*From the Department s of Med icine and Ph ysiology, Th e University of Texas Health Ce nter at T yler. Suppor ted in pa rt by a gran t from th e Ray and Ipha Morrow Research Fund . Manuscript received November 29, 1993; revision accepted April 5,1994. Reprin t requests: Dr. Carter, Depart men t of Medicin e and Physiology , Box 2003, The University of Texas Health Center, Tyl er, Texas 75710 1730

ANCOV A= ana lys is of cova ria n ce; Dco=diffu sin g ca pa city for carbon monoxide; HR=heart rate; 0 2P= oxygen pul se; VE=exer cise ventilation; VT= tida l volume; VEm ax = m aximal exerc ise vent ila tion

Key words: COPD; gende r; ventilation; work capacity

Effects of Airway Obstruction on Work Capacity and Ventilation in COPD (Carter, Nicotra , Huber)

data , the difference in tobacco smoking rates for men and women had narrowed to less than four percentage poin ts by 1987 . The smoking rate for women now is thought to approximate that of men and it is project ed to surpass that of men by th e yea r 2000. The increased pr evalence of smoking in women has farreaching implications concerning diseases of th e lung, especially if women are shown to be more susceptible to cigarette-associated lung disease. Gender-specific differences in pulmonary function and exercise performance in normal individuals ar e recognized , with men achieving higher work performances, as measured by the maximal oxygen uptake (Voz) in abso lute (m L / min) and relat ive (m L / kg-min?" ), terms. Men ar e also mo re likely to lead a restricted life -style at an equivalent degree of p ulmonary disease than are women. P This may im ply that men are mo re debilitated than women when th ey first seek medical attention or that the physical work demands are greater for men than women , such that men experience more symptoms than wom en at th e same relati ve levels of functional capacity. This, in pa rt , would reflect diff er ences in mean functional capacities known to exist between th e sexes." Because of an absence of comparative data assessing work performance in men and women with COPD, we perform ed a ret rospective analysis based on our existing exercise gas exchange database. Specifically, we wanted to det ermine if differences in exercise capacity exist between male and female patients with specific level s of airway obstruction, and if declines in functional capacity ar e diff erent betw een the sexes. M ETHODS

Subj ects and Study Design Four hundred seventeen m en and wom en with COPD , 55 to 85 years of age, were studied . We exclude d an y patient from the ana lysis who was younger than 55 yea rs of age, so that a mor e un iform com parison cou ld be mad e betw een men and women given th e deg ree of airway obstruction studied. All patients in th e dat abase underwent ph ysiologic testin g as part of their clinical eva luation for lung disea se or for entran ce into a pulmonary rehabilitation program. Disease-fr ee subjects (16 women and 13 men) of sim ilar age serv ed as controls. Whil e some of th ese individ uals had a histor y of prior smo king on qu estioning, each was fr ee of any significant declin e in pulm ona ry function and none was smo king at th e time of this study . All control subjects had und er gone sim ilar ph ysiologic stud ies as part of a preventive med icin e scree ning pr ogr am . All pati ent s with COPD ente red int o this study met th e followin g criter ia: (1) F EV l to FV C rat io less than 75%; (2) total lun g ca pac ity grea ter th an 80% of pr ed icted ; (3) the abilit y to perform exercise testin g; and (4) th e ability to give informed written consent in com pliance with instit utiona l policies. Exclud ed wer e those pati ents with known cardiac , ren al, or endocrine disease, and pati ents experiencing claudicati on limiting exercise cap acit y, mus culoskeletal pa in, or syncope , or significant electroca rd iogra phic ST-T depression or arrhythmia on exercise testin g. All pati ent s tested wer e receiving a stable drug regimen and wer e in stable condition.

Lung Function Pulm onar y fun ction testin g for controls and pati ent s with CO PO was identi cal. Spirogr am s wer e pe rfo rme d using a rolling seal spirome te r (P. K. Morgan , Dallas). Lun g volumes were measure d by body pleth ysmograph y (Cardiopulmonary Instruments, Houston ). Th e resting diffusing ca paci ty of the lun g for carbon monoxide (Dco) was measured by th e single-brea th technique of Jones and Mead ." Th e norma l valu es of Cra po et als were used to calculate age - and ge nde r- predicted norm al spirome tric values. Norma l predi cted lun g volum es wer e der ived from th e eq uations of Goldm an and Becklake? (women) and Boren et ap o (men). Pred ict ion of Dco was based on th e dat a of Make et aLII All values report ed for lun g fun ction testin g wer e obta ined aft er bron chodilator ther ap y by meter ed-dose inh aler (albuterol: total drug deli ver ed , 180 /lg) for both men and wom en . All pati ents had pri or experience with the use of a meter ed-dose inha ler and wer e observed during the administrati on of the medi cation. Th e dosing ' prot ocol followed was to ad mi niste r one puff , wait 10 min , then ad m iniste r one additiona l puff and wait 10 additional min before performing lung func tion testing. Lung function testin g was perform ed according to American Thoracic Society (ATS) criteria. l2 Th e best study performed by th e pati ent was used in the final analysis of the dat a. Th e best study was defined as that stud y whi ch met ATS crite ria and was the best effort as judg ed by the flow volume loop. All calculations wer e m ad e by personal com put er (E BS soft ware and IBM PC, Dallas) inte rface d to the measure me nt instrumen t. Pulmonar y fun ction indic es wer e used to classify pati ent s according to the degr ee of airflow limi tat ion by the m eth od of Gri ppi et al. 13 Mild airflow lim itat ion was defined as a forced expir at ory volum e in I s (FE Vl)/ forccd vita l ca paci ty (F VC) rat io of betw een 60.5 and 69.5 % (F EVJ! FVC rati o 2::60.5 and < 69.5 %). Th ose with moderat e airway obstruct ion had an F EV l/FVC rati o 2::50 .5 and < 60.5 %, whil e th ose with severe airwav obstruc tion had an FEVJ! F VC of < 50 .5 %. All pat ient s wer e tes ted afte r br onchodil ator ad m inistratio n. Thos e pati ent s with a postb ronchodilat or response of grea ter th an 20 % wer e excluded . A br onchodilat or response grea ter than 20 % sign ifies an asthma tic component and thu s a differ ent path ologic pro cess.

Exercise Testin g Exercise testing was perf orm ed 30 to 60 m in after inhaled bronchodilator therapy administered by th e method described above . Following info rm ed consent, pati ent s were prepared for exercise testing . Each pati ent was instructed and given a short practic e trial of pedaling on an electronically braked watt cycle ergome ter (Kern 2, Mijnhardt, Odijk , Holland) with the seat height adjusted to 100% knee exte nsion ; a short rest peri od followed . A mouthpiece connec ted to a nonr ebreathing valve (Hans Rud olph, Kansas City, Mo) was positioned in th e subject's mouth. Th e pati ents end-tida l gas values wer e inspect ed to ensure th at the readings wer e with in acce ptable ran ges. Th e subject th en br eath ed qu ietl y until th e breathing patt ern sta bilized, dem onstra ting a consiste nt end-tidal CO 2. Th e subject began ped aling at a fr equ ency of 50 to 60 revoluti ons per minute (rpm) at 0 load . Afte r 3 m in of unl oad ed pedaling, work loads wer e adjusted eac h mi nut e by 10 to 20 W . Work load incre me nts were selected based on pulmonar y fun ction severity and patient history. Th e method used th e estima ted work load a patient could complete given his or her estima ted ma ximal ventilation.!" A work load was selecte d to elicit a maximal exercise response at 6 to 10 min into the exercise prot ocol (wor k load range, 10 to 20 W/ m in). Th e controls perform ed sim ilar testin g, with the exce ption that work load incre me nts of 10 to 30 W / m in wer e used to elicit a maximal response in 6 to 10 min . Exercise gas exchange dat a wer e obta ined utilizing an automat ed exercise testing system, as pr eviously described . IS Arteri al CHEST / 106/ 6/ DECEMBER, 1994

1731

T able I-Demographic Chara ct eri stics of Men and W om en by Degree of Airflow Limitation Classification* Women Variables

Controls (I 6)

Mild (23)

Moderate (42)

Severe (58)

Age, yr BSA, m 2 BM1, kg/ m 2 Ht, cm Wt, kg Smoking Hx, pk-yr

65.5±7.8 1.69±O.15 O.253±0.056 162.1±5.7 66.1 ± 13.6 7.8± 15.6

64.8 ± 6.4t 1.69 ± 0.16t 0.252±O.059t 162.1 ±4.2t 65.0± is.u 35.1 ±25.91

65.0±5.2t 1.63±O.19t 0.237 ± 0.053 t 160.8 ±5.4t 61.4 ± 14.8t 54.8 ±35.91

63.7±5.8t 1.63±0.17t 0.227 ±O.055t 162.8±5.5t 59.5± 14.6t 58.5± 33.01

Men Variables

Contro ls (I3 )

Mild (32)

Moderate (57)

Severe (I 76)

Age, yr BSA, m 2 BMI, kg/ m 2 Ht, cm Wt, kg Smoking Hx, pk-yr

60.0±4.7 2.08 ± 0.20 0.292 ± 0.040 176.6 ± 9.3 91.1± 14.7 34.1±27.5§

65.3± 6.5t 1.96±0.211 0.261±0.0441 174.7±7.9t 81.3 ± 16.71 60.1 ±29.0t§

66.3±6.2t 1.91 ± 0.18t 0.247 ± 0.045t 175.3±6.2t 75.7 ± 14.7t 65.9± 36.7t§

66.3±6.3t 1.89±0.18 t 0.231 ±0.0361 177.0 ± 7.5t 72.7 ± 12.91 67.4±33.61§

*BSA= body surface area; BMI=b ody mass index; Ht = height; Wt=w eight ; Hx=h istory. [No t significant at p>0.05. [Statistically significant difference from the value at the immediate left at at least the p<0.05 level. §Denotes statistically significant differences from the values for women at the same disease classification at at least the p<0.02 level. oxyge n satura tions wer e monit ored continuously by noninvasive oximetr y (model 4720 I-A , Hew lett Packard , Ch elmsford , Mass). Th e elect roca rdiogram waveform and ca rdia c freq uency were monitored thr oughou t rest, exe rcise, and recovery periods using a I2 -lead ECG (Q uinton Q-2 000 , Quinton Instrum ents, Seat tle). Blood pressur e was obtain ed by sta ndard cu ff and ausculta tory techn iqu es. In addi tio n, all subjects were constan tly enco ura ged to per for m as muc h work as possible. Data Analysis Group mean dat a were genera ted using a system (Statistical Analysis System , SAS Institute, Ca ry, NC) for a com puter (VAX).16 Each end point was sta tistically com pared acros s adjacen t COPD categ ories within each gend er separate ly. Th e patt ern s were then info rmally compared across sexes. Data were analyzed by gender and deg ree of airway obstruct ion. Freq uency tabl es and x2 ana lysis were used to deter m ine d iffer ences in the fr eq uency of occ ur rence of selected var iabl es. Analysis of covaria nce (ANCOVA) was used to q ua ntita te COPD differ en ces within each gen der. An option (LSMEANS) of th e progra m (SAS Pr oc GL M) was used to ob tain p values for ad justed pai rwise com pa risons. Age was used as a cova ria te in all ana lyses, whil e both age an d maximal heart ra te were included as covariates in the ana lysis of the maximal exercise respons e. Th e purpose of the cova riate an alysis of variance is to math em aticall y con tro l for a detect ed significa nt differ ence in one or more of th e depe nden t variab les. By using ANCOV A, a degr ee of freedom is sacrificed for th e increased precision gained in the ana lysis. Linea r regression ana lyses were perform ed . Sepa rate regr ession models for each ge nde r wer e fit when com pa ring V0 2 at varying levels of FEV l . Multiple linear regression techniqu es for unba lanced data using the GLM proce d ure in SAS were used to investigat e relat ionships amo ng the variables of interest. We used dumm y variabl es acco rding to the techn iq ue described by Kleinbaum and Kupper.! " Raw means ± SDs are repo rted in the tab les; however , the significance report ed is based on the ANCOV A analysis of adjusted least squares mean s. Maxima l exercise da ta repr esent ed th e last 30 s of dat a collected for th e symptom -lim ited maximal exercise test. 1732

R ESULTS

Dem ographic charact eristics of the men (n =278) and women (n = 139) studied are sum ma rized in Table 1. Ages ranged from 55 to 85 years and 55 to 83 yea rs for men and women , respectively. Men wer e, on average, 25 kg heavier and 14.5 em taller than the wome n studied. Bod y weight was the sam e for wome n across disease classificati ons. Men, however , dem onstrated a pr ogressive reduction in bod y weig ht across disease severity classifications. Control men were 11 kg heavier , when com pared with male patients with mild COPD. Bod y weight declined by an additional 5.6 and 3.0 kg for men with moderat e and severe COPD, when com pared wit h ma le patient s with mild to moderate COPD. Th e only statistically significant difference noted for age was found between the controls and obstruc ted men . Overall , female tobacco smokers had fewer pack-years of smoking history than did men (43.8 vs 63.0, p < .OOOl ), while the control men presented with man y more pack- years than the fem ale controls. Mean packyea rs differ ed significant ly between patients with mild , moderate, and severe disease, respectively. Additionally, the number of lifeti me non smokers among women with COPD was great er tha n among men with COPD (4.2% vs 1.3% of the women and men , p
Effec ts of Airway Obstruction on Work Capacity and Ventilation in COPO (Carter, Nicotra, Huber)

Table 2-Spirometric Data for Men and Women by Degree of Airflow Limitation Classification Classification Variables]

Wom en F VC, L % pred FVC, % FEVJ, L % pred FEV 1, % FEVi/ FVC, % FEF25-75, L/s PEF, L /min MVV, L/min Men FVC, L % pred FVC , % FEV 1, L % pred, FEV I , % F EVi/FVC, % FEF 25-75, L/ s PEF, L/min MVV, L/min

Controls

Mild

Moderat e

Severe

2.83±0.45 95.6±9.8 2.24±0.37 97.7± 10.8 79.3±3.1 2.05±0.58 350.2±95.9 77.4±23.3

2.48 ± 0.62* 83.3 ± 21.9* 1.63 ± 0.41* 70.7± 18.9* 65.7±2.6* 0.75 ±0.32* 266.5 ± 83.8* 53.2± 19.8*

2.25±0.6It 77.0± 16.4t 1.16±0.40* 51.4± 15.6* 51.2 ±4.6* 0.35±0.17* 213.7 ± 76.4* 44.4 ±21.0t

2.16±0.46* 71.5 ± 14.6* 0.78±0.22* 33.2±9.5* 36.3±5.2* 0.19±0.07* 157.9±65.2* 31.5± 18.0*

4.18 ±0.45 90.5 ± 11.5 3.31 ±0.35 90.8 ±8.7 79.1 ± 2.7 2.89±0.55 620.2± 127.6 121.8±33.3

3.27±0.84* 73.9±17.9* 2.11±0.55* 61.2± 14.9* 64.5±2.7* 1.04±0.36* 374.3 ± 98.6* 72.2 ±23.7*

3.32±0.97 t 75.1±20.It 1.70±0.50* 49.5±13.7* 51.1 ±4.47* 0.51 ±0.23* 305.6±108.6* 63.1 ±23.7t

3.18±0.80t 70.2± 16.5 t 1.06±0.31* 30.2±8.6* 33.3±5.7* 0.27 ±0.21 * 225.4 ± 80.7* 41.6± 18.5 *

*Statistically significant difference from the value at the imm ediate left at at least the p<0.05 level adjusting for age by ANCOV A. [Not significant at p>0.05. tFVC=forced vital capacity; PEF=peak expiratory flow; MVV=maximal voluntary ventilation; FEV I = forced expiratory volume in I s; FEF25_75=maximal mid-expiratory flow.

creasing pack-years of cigarette smoking for each gender (Tables 1 and 2). Maximal exercise gas exchange values are presented in Table 3 for men and women by level of airway obstruction. Absolute work performance was less for women and each gender demonstrated a decline in work capacity as airway obstruction pro gressed from mild to severe. Men lost a significant portion of their functional ability (V02) early in the disease process , with a significant decline in peak oxygen consumption between the control subjects and those with mild COPD. Women, however, started at lower absolute work capacities, yet unlike their ma le counterparts, no significant decrease in functional capacity (V02) was observed until moderate COPD was present. Female patients with severe COPD had significantly lower oxygen consumptions than those with moderate disease . Similar differences were noted when oxygen consumption was expressed relative to body weight (mL /kg.min- 1) . The maximal work respiratory gas exchange ratios (R=VC02/V02) were equivalent between men and women at all severity levels, with values in the range of 1.00 to 1.10. In men, the maximal heart rate (HR) was decreased with mild COPD, compared with controls (p<0.05) . All other maximal HRs were equivalent across disease classifications for men and women. The oxygen pulse (02P ; ie, Vo2/HR), an indicator of cardiac stroke volume,14,18 was shown to decline across disease severity groups. For men, significant decreases were noted between controls and those with mild COPD and between moderate and

severe disease classification . For women, the 02P did not decrease in the mild COPD group. With moderate and severe COPD, declines in the 02P were seen. Maximal exercise ventilation (VEmax) also de creased as disease worsened. For men, a significant decrease was noted for patients with mild disease, resulting from a reduction in tidal volume (VT) with stab le respiratory rate (RR); the decrease continued with progression of COPD. For women, maximal exercise ventilation was not significantly reduced until moderate CO PO was present and declined further in patients with severe COPD . We then compared each control and patient with their age- and gender-specific predicted value . Oxygen pulse (02P), and HR as a percent of predicted for men and women are shown in Figure 1. For women, although the maximal oxygen consumption as a percent of predicted steadily decreased with increasing disease severity, a statistically significant decrease was observed for the severely obstructed group only. For men, each COPD severity classification resulted in a significant loss in percent of predicted oxygen consumption . While the 02P trended downward for increasing airway obstruction in women, a statistical difference was not obtained until the disease was severe . For men, however, a significant loss in the 02P was detected for those with mild and severe COPD. These differences were seen even though small differences in maximal HR were controlled for by use of a covariate ana lysis of variance. Both men and women significantly decreased their maximal ventilation as airway obstruction increased (Table 3). Only CHEST / 106 / 6 / DECEMBER, 1994

1733

Table 3-MaxiTrUlI Exercise Gas Exchange Data for Men and Women by Degree of Airflow Limitation Classification Classification Variables] Wom en Work max , W VE, L/min RR, breaths/min VT, mL Vo 2, mL /min VC02, mL /min R (VC02lV02) Vo 2, mL /kg .min- 1 VC02, m l. Zkg-min'"! lIR , bpm 02P (Vo 2/HR) Cardiac output (Q), L Breathing reserve, L Men Work max, W VE, L/min RR, breaths/min VT, mL V02, mL /min Vco2lVO,mL/ m in2) R (VC02lV0 2 ) Vo 2, m l. Zkg-rnin"! VC02, m L/kg -mtn "! HR, bpm 02P (Vo2lH R) Cardiac output (Q ), L Breathing reserve, L

Controls

Mild

Moderate

63.9 ± 25.4 42.6± 16.5 37.2 ± 11.2 1,195.7±415.2 1,059.1 ±344.1 1,108 .1 ± 457.6 1.02±0.14 16.1±4.8 16.8±6.6 139±7.4 7.82±2.4 12.26±2.1O 34.7±24.2

55.1 ±22.0* 39.9±11.9* 34.1 ±8.2* 1,215 ±345.5* 996.7±266.3* 1,128 .5 ± 307 .4* 1.03±0.1l * 15.6±4.1 * 16.2±5.1* 139.6±5.8* 7.61 ±2.06* 11.88 ± 1.62* 13.2±16.8t

47.8± 19.0t 33.9±8.2t 34.0±6.4* 1,023.9 ± 295.5t 837.6±235.9t 830 .1 ±245.8t 0.99±0.1l* 13.9±3.5t 13.8±3.7t 139.3 ± 4.7* 6.44 ± 1.7t 10.91 ± 1.44t 10.5 ± 19.2*

34.3± 16.9 t 26.1±7.2t 30.3±7.2t 897.7±233.9* 660.5± 198.2t 594.9 ± 221.5t 0.89±0.1l t 1l.3±3.0t 10.1 ± 3.3 t 140.7±5.3* 5.2± 1.6t 9.83 ± 1.21 t 5.3± 16.6t

130.8±25.0 7l.3± 13.4 33.1 ±7.5 2,246 .9 ±585.3 2,01O.0±392.0 2,008.4 ± 409.3 1.00±0.12 22.5±5.2 22.';±5.0 144.0±4.2 15.3±2.6 18.06 ± 2.39 51.6±35.7

79.2±35. 1t 51.5± 18.5t 32.4±8.5* 1,621.0 ± 480.0t 1,370.0±457.9t 1,406.8 ± 566 .2t 1.01 ± 0.13 * 17.0±5.56t 17.6±7.1f 139.3±5.9t 1O.6±3.3t 14.16±2.79t 20.7±19.0t

65.5±31.0t 48.3±14.2* 32.7±5.8* 1,499.8±418.2* 1,212.2 ± 400.8* 1,2118.8±456.6* 0.99±0.14* 16.2±4.9* 16.3±6.0* 138.3±5.6* 9.58±2.96* 13.19±2.44* 15.5±23.1*

48.9±27.6t 37.1 ± 11.4t 31.1 ±6.6* 1,221.2 ± 341.4 t 979 .8 ±320.6t 920.0±364.8t 0.92±0.1l t 13.5± 3.8 t 12.7±4.6t 138.3 ± 5.64 * 7.88±2.35t 11.77±1.96t 4.4±17.6t

Severe

*Not sign ificant at p>0.05. tStatistically significant difference from the valu e at the immediate left at least the p<0.05 level, by ANOV A. lRH=respiratory rat e ; VT = tota l ventilation; R = respi ratory quotient; VE = exercise ventilation Vo2=oxygen uptake or consumption; Vco2=carbon d ioxide production; HR=heart rat e; 02P=oxygen pulse .

in men with moderate airway obstruction did the decrease fail to reach statistical significance. Both the male and female patients manifested reduced ventilatory reserve , ie, the difference between the actual VEmax and the possib le VEmax estimated from the FEV 1· The relationship of functional capacity (Vo 2 mL/ min) to the degree of airway obstruction (FEV 1) in men and women was assessed (Fig 2). Using regression techniques, two separate regression models were warranted. The models were as follows for men and women, respectively: Men : V0 2 mL /min =532+414 (FE VI) r =0.66 p
Cardiac output (Q) (Table 3) was estimated for the peak wor k load achieved by each individual using the method of Sackner et al. 19 Results demonstrate that the control subjects' values were within the expected range. Men with mild COPD had a low estimated cardiac output (p
Effects of Airway Obstruction on Wor k Capacity and Ventilation in COPO (Carter , Nicotra, Huber)

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their functional work capacities as airway obstruction increased . T he reasons for the initial dramatic decline in functional work capacity noted in the me n is not completely understood . It might be asked if our male con tro ls have higher maximal oxygen consumption values than the average nonobstructed 60- to 65year-old. This is not the case, however , in that Seals et al20 and Hagberg et al21 ha ve reported oxygen consumption values of approximately 25 mL / kg.min- I , while Yerg et al 22 found that sedentary men had oxygen consumption values averaging 2,220 mL /min; the American Hear t Association'e' also has published similar maximal oxygen consumption data for men of th is age . Thus, our values for controls ar e in accord with or , if anything, not higher but actually lower than published values. On e possible explanation for the lower measur ed work capacity in our male controls could be related to sedentary living and excess bod y weight. Our men averaged 91 kg, which is more than that predic ted for their height. Thus, our ma le controls may not be represen tative in this respect. The bias present ed by excess body weight

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E1500 N

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,

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FIGURE 2. Regr ession lines for fun ctional capacity (V02) in men (A) and women (8) with advancing CO PO. The regression lines ar e significantly different with respect to both the intercept p
CHEST / 106 / 6 / DECEMBER, 1994

1735

would, how ever , make it more difficult to detect a real or significant diff erence in Vo 2. Th e question could also be raised th at our control fem ale maximal oxygen consumption values were less th an that of th e ave rage 65-year- old fem ale popu lati on , biasing detecti on of a declin e in fun ctional work capacity . Again, thi s does not appea r to be the case , since our contro l values were com pa rab le to th e data published by others .2o.22 Could work perf orm an ce be limited in men attr ibut abl e to significant decr eases in pulmonar y ventilation (maximal exercise ven tilation)? Both men and wome n with mild COPD ac hieved 65% of th eir age - and gende r-specific pr edi cted maximal exerc ise ventil ati on . Th is would im ply a ventilatory reser ve of 35% in these patients, wh ich is conside red good and is grea ter th an th e 30 % reserv e valu e commonly suggestive of clinically import ant ventilat ory limitation. Thus, ventilatory impairm ent cannot be the only contributor to th e measur ed decr em ent in functiona l work capaci ty noted for men with mild COPD. Overall, VEmax did decrease significantly for men and wome n as airway obstruc tion incr eased . Th is is a well-recognized find ing, especially in patient s with adv anced CO PD.1,24.26 In com pa rison, our controls did not excee d 61% of th eir pr edi cted maxim al vent ilation, repr esenting a good ventilatory reser ve base d on an expected reser ve val ue of at least 30 % of predi cted maximal vent ilation ; 70% of the predi cted resting maximal ventila tion is th e upper limit of exercise peak ventilation in normal subjects, thus providi ng a 30% reser ve , ie, 100%-70 %=30% reser ve. With mild airway obstr uction, VE max averaged 65% of pr ed icted in men and wome n alike. Moderate airway d isease incr eased the values to between 75 and 80% (dec reas ing th e mean ventilatory reser ve to 20 to 25%), whil e severe disease elevated th e values to betw een 85 and 90% of pr ed icted (mean ventil atory reserv e of only 10 to 15% pr edi cted maximum). On an individual basis, some patients with adva nce d COPD eve n exce ede d th eir ventilator y limits, pred icted from th eir resting pulmonar y function values, which is consistent with th e available liter ature.15,27·29 Some of our controls we re ex-smo kers, although none had clinical evide nce of lun g disease (if the smoking had any effect on con tro l exe rcise values, it would have led to a sma ller d ifferen ce between controls and pati ents in th e various parameters). In fema le con tro ls, the smoking history was minimal. In male controls, however , ther e was a substantial smokin g history. Th e lower functional ca paci ty displayed by men with mild COPD may be related to decreased cardiac performance. We continuously meas ure d th e 0 2P, an indirect estimate of cardiac stroke volume (02P 1736

mL/beat= Vo 2/HR=SVX C[a- v]02) during incr ement al exercise testing. Th e 0 2P was lower th an control values at all submax ima l work load s, which ag ree with pr evious report s for pati ents with COPD .14.30,31 At eq uiva lent peak HR s, R values, and similar ages, th e 0 2P significantly declin ed fr om a value of 102.4 to 78.9 % of pr ed icted , com pa ring control men to th ose with mild COPD . These data sugges t a significan t decline in ca rdiac stroke volume with a corres ponding reduct ion in cardiac output, which will significantly limit fun cti onal capacity. We con firmed this reducti on in estima ted ca rdiac output for men with mild airway obstruc tion, using th e regression eq uation developed by Sackne r et aJ.l9 The cardiac output estima tes using thi s technique confirm ed th e decreases noted by measur em ent of th e 0 2P and isolated the decr ease to card iac stroke volume since sim ilar HR s were obta ined . Th e mech an ism for th e observed reduction in stroke volume is uncl ear from th e present data. Decreases in stroke volume are known to occur as a result of coronary artery disease , card iac myopathies, system ic hypertension , or att ributable to chronic pulmonar y hyperten sion related to th e lun g di sease. We atte m pted to elim ina te pati ents with cardiac disease as a result of our pati ent scree ning pro cedure. T he presence of chronic pulm onar y hyp ertension in pa tien ts with mild COP D seems unlik ely. Acute and chronic decond iti oning are also known to decr ease ca rd iac stroke volume. 32 Thus, th e strongest over all contributor to a decr ease in ca rd iac str oke volume may result fr om an accelera ted deconditioning pr ocess an d may be secondary to alte ra tions in th e myoca rdi um, to im pairme nt in th e control of capacitan ce vessels, or to both .32 The deconditioning hypoth esis may ha ve add itiona l support from th e 5-year age diff er enc e not ed between male controls and patients with mild COPD. This age diff erenc e occurred whe n men would be retiring fr om th e work place and th us decreasing th eir ph ysical work ca paci ty. Howeve r, we did attempt to control for th is age differ en ce by use of ANCOV A adjusting for age . Also, it should be noted th at eve n th ough our controls we re younge r, th ey were hea vier , and th eir body weight was increased sugge sting th at th ey to we re leading a sedenta ry life. The decline in funct ional capa city becomes linear after the initi al decr ease in men ; thi s would tend to suppo rt th e decond itioning hyp othesis. Addi tional support for th is explanation is found by th e analysis of our corre latio n coefficients. W he n maximal work output is corre lated to per cent pr edi cted oxyge n pulse, a correlation coefficient of 0.42 is noted for wome n an d 0.71 for men . This suggests tha t th e decline in work ca pac ity or fun cti onal ca pac ity is mor e tightly cou pled to a reduction in stro ke volume for men , as com pa red with wom en.

Effects of Airway Obstruction on Work Capacity and Ventilation in COPO (Carter, Nicotra , Huber)

This finding has far-reaching implications. First, rehabilitation efforts may be more successful in increasing functional capacity in men when mild disease is present. Second , exercise training could be expected to increase functional capacity to near normal limits when the disease is mild . Third, with the disease process left unchecked, progression will occur and ventilatory limitation will ensue . As a result of increasing ventilatory limitation, the patient's ability to respond to physical activity will be seriously impaired. We have also shown that men, unlike women, lose body weight from the onset of the disease process, as compared with controls . These changes were confirmed by the body mass index, which decreased across all airway obstruction classifications for men, but no significant differences were noted for the women. While we acknowledge that our male controls were heavy, this does not explain the additional decrease noted for increasing levels of COPD severity. The potential underlying reasons for changes in body weight are numerous. First, increases in total 24-h energy expenditure attributable to the altered mechanics of breathing can result in the expenditure of significant amounts of calories and thus reduce body weight. Second , with increasing airway obstruction, eating becomes more difficult, for a variety of reasons, including increased dyspnea, thus leading to reduced caloric intake. Third, anorexia may develop with disease progression. Fourth, attributable to a combination of factors , body composition will change resulting in a lossof lean muscle mass and an increase in body fat. However, the rate of change for muscle mass and body fat are not directly coupled; thus , weight lossmay occur and this will be reflected on the bathroom scale. The absence of decline in overall body weight in women is another matter. Several possible explanations exist for this. First, the underlying lung disease may somehow be different. Second, eating patterns in women may be different from men. Third, there may be an unrecognized hormonal reason for protection of body weight in women. Finally, women may have already minimized muscle mass and thus have adequate caloric intake to offset the additional caloric burden imposed by advancing airway obstruction. Lastly, our data show that women presented with 20 fewer years of tobacco smoking history than their male counterparts. When all the patients were considered, the women presented with fewer pack-years of smoking history at a time when their pulmonary function indices had already declined to values equal to men with significantly more cigarette exposure histories. Greater tobacco consumption for men, at least as expressed by smoking histories, was consistent through all levels of airway obstruction studied. Thus,

women had less cigarette exposure, as defined by pack-years smoking history, yet presented with similar degrees of airway obstruction. This observation raises a serious question whether women are more susceptible to cigarette smokeinduced airway obstruction than are men . In evaluating this hypothesis, we realized that we had a substantial number of lifetime nonsmokers among the women with COPD. To assess the question of increased susceptibility of women to cigarette smoke, we compared only the smoking individuals. This comparison confirmed a highly significant gender difference with respect to smoking history between men and women with mild airway disease (54.5 ± 32.8 vs 26±27.2 pack-years, p<0.003) . Several possibilities exist that may partially explain differences with respect to the tobacco smoking history noted for the men and women. First, women may truly be more susceptible to cigarette smoke, developing airway obstruction with lesser degrees of exposure. Second, the smoking exposure histories for women may be inaccurate, because smoking is more taboo for women, especially older women . This conceivably might lead to a systematic underestimation by the women of their smoking histories. Third, while no solid evidence exists, some women may have been exposed to second-hand cigarette smoke from their smoking spouse and this may have had an effect on the outcome measurements. If second-hand smoke proves to be associated with developing lung disease, we may have consistently underestimated smoke exposure, especially in women. Lastly, women smoke differently than men and consume different brands of cigarettes, which may Significantly influence medical outcorne.P Animal models and epidemiologic data suggest gender differences related to tobacco smoking; thus, it is possible that our women had actual dose levels equal to or in fact greater than their male counterparts. More data are needed to address this question fully . If there does exist a gender-determined difference between men and women in regard to the development of airway obstruction, there are some possible explanations. There may exist a hormonal or physiologic difference for women, which leads to less tolerance of cigarette smoke . Scanty data suggest that this may be the case.34-36 Female rats, when exposed to cigarette smoke for 180 days, will significantly increase the number of goblet cells, compared with male animals, conceivably implying that women may be more susceptible to bronchitis than men.F There is the suggestion by Tager et aI38 and Speizer et aI39 that the population attributable risk percent for development of COPD is greater for women than for men. Additionally, prevalence rates for COPD for men and women differ based on the age of the cohort, CHEST / 106 / 6 / DECEMBER, 1994

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with women having a higher pr evalence rates between the ages of 55 to 64 years, and men having higher rates above 65 years of age .36 This would suggest that women might present with lower smoking histories, compared with men, and this is what we experienced. In summary , the present study documents that numerous differences exist between the loss of functional work capacity in men and women with early COPD, with men with mild COPD experiencing a greater loss than their female counterparts. The exact underlying mechanisms responsible for the decline in functional capacity have yet to be identified, but they appear to be related primarily to a significant decrease in cardiac performance secondary to chronic deconditioning and airway obstruction. Differ ences in body weight for men suggest that caloric intake and caloric exp enditure are altered more for men than women with advancing COPD . These findings strongly suggest that rehabilitation and exercise training should be initiated early in the disease process. Th ere is also the suggestion that women may be more susceptible to cigarette-induced pulmonary dysfunction than men. Clearly, additional research is warranted to address these concerns. Ideally , longitudinal studies should be designed to better address the issues raised in this study. REFEH ENCES

2 3 4 5 6 7 8 9 10

11 12 13

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Effects of Airway Obstructionon Work Capacityand Ventilation in COPO (Carter. Nicotra. Huber)

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