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Oxygen Consumption of Respiratory Muscles in Patients With COPD
Oxygen Consumption of Respiratory Muscles in Patients With COPD* Chiyohiko Shindoh, M.D.; Wataro Hida, M.D., F.C.C.P.; Yoshihiro Kikuchi, M.D.; Osamu Taguchi, M.D.; Hiroshi Miki, M.D.; Tamotsu Takishima, M.D., F.C.C.P.; and Kunio Shirato, M.D. We measured the oxygen consumption (""o 2 ) of respiratory muscles in 8 COPD patients and 12 agematched healthy subjects using a closed circuit device which allows a continuous increase in external dead space and is equipped with a 9-L Collins spirometer. Furthermore, we measured simultaneously mouth occlusion pressure at 0.1 s of inspiration (P0.1), minute ventilation (""E), and other ventilatory parameters during the measurement of total 2 (""o2 tot). We found that the logarithm of ""o1 tot (log""o1 tot) had a good correlation with ""E in both groups. The mean slope of the regression line of log""o 2 tot and ""E (6log""o1 tot/6""E) of COPD patients was significantly higher than that of normal subjects (p < 0.001). However, the mean Y-intercept (metabolic ""o2 [""o 2 met]) of the regression lines did not differ between the two groups. The P0.1 in COPD patients was higher than that in normal
subjects at the corresponding dead space loading. However, the ""E did not differ between the two groups except for at rest and the first 1 min after dead space loading. These results suggest that the 2 of respiratory muscles in patients with COPD is higher at given ventilation compared with that in age-matched normal subjects and that this increased ""o 2 partly may be due to an augmented ventilatory drive. (Cheat 1994; 105: 790-97)
previous studies 1· 6 have shown that the oxygen cost of respiratory muscles in patients with COPD increases more than that of normal subjects when they increase minute ventilation (VE). However, in most studies, oxygen consumption (Vo 2 ) of respiratory muscles has been measured in patients with COPD whose ages ranged from 44 to 72 years and in normal subjects, for the most part, from 19 to 47 years of age. Because most of the patients with COPD are relatively elderly subjects and because we have recently found that the Vo 2 of respiratory muscles increases with aging in normal subjects/ we should compare the respiratory Vo 2 in patients with COPD with that of normal subjects who are in an age-matched group. In our previous study/ VE was used as a parameter of respiratory muscle task, and the slope of the regression line between logarithm of total Vo 2 (logVo 2tot) and VE (~logVo 2 toti~VE) expressed the overall respiratory muscle efficiency. However, because the VE in patients with COPD is generally restricted by airflow obstruction, the ratio
(~logVo 2 toti~VE) may possibly be higher than that in normal subjects. Mouth occlusion pressure (PO.l)H has been widely used as the output of the respiratory controller not only in normal subjects, but also in COPD patients. 9 Fales et al 10 also reported that Vo 2 in skeletal muscle changed according to stimulation frequencies . Since an increase in stimulation frequency is caused by an increase in respiratory drive, our hypothesis is that the energy cost of muscle contraction may increase with an associated increase in respiratory drive. In the present study, we measured total Vo 2 (Vo 2tot), VE, PO.l, and other ventilatory variables during continuously expandable dead space loading in patients with COPD and age-matched normal subjects.
""0
*From the First Department of Internal Medicine, Tohoku University School ofMedicine, Sendai, Japan. This worl< was supported by the Grant-in-Aid for Developmental Scientific Research (No. 01870037) of the Ministry of Education, Science and Culture, Japan. Manuscript received November 24, 1992; revision accepted July I, 1993. Reprint requests: Dr. Shirato, 1st Department of Internal Medicine, Tohoku University, 1-1 Seiryo machi, Aoha-ku, Sendai 980, Japan
790
""0
Cst= static lung compliance; FETC01 =end-tidal C01 fraction; FRC = funCtional residual capacity; log'(To1tur= logBrithm of total oxygen consumption; P(f.I = mouth occlusion pres· sure at 0.1 s of inspiration; PEmax = maximum static expiratory pressure; Punax = maximum static inspiratory _pressure; Rl ., fulmonary resistance; RV = res1dual vofume; TLC '" tota lung capacity; ~E = minute ventilation; '(To~ = metaboliC oxygen consumption; ~o1 res = respiratory muscle oxygen consumption; ~o1 lol = toial oxygen consumption
METHODS
Subjects We studied 8 patients with COPD (66 ± 3 years) and 12 elderly normal subjects (62 ± 2 years) . The patients with COPD were diagnosed by clinical symptoms, chest roentgenographic findings, and lung function data, and the diagnoses of pulmonary emphysema and chronic bronchitis were consistent with the diagnostic standards of the American Thoracic Society." All patients with COPD were in a stable clinical state and had shown no substantial changes in pulmonary function during the previous 6 months. Bronchodilator usage was withheld for at least 16 h before the experiments. Normal subjects, who were selected from a group of active workers or ex-workers (> 63 years) of an electric company with the company's coordination , and did not know about the aim of the present study, were free Oxygen Consumption of Respiratory Muscles in COPD Patients (Shindoh et at)
Table 1-Anthropometric Charocterinica of Age-Matched Normal Subject. and Chronic Olmrvctioe Pulmona'll lJi3eaae lbtienl3 Body Subject No.
Sex
Age, yr
Height, em
Weight, kg
Surface Area, m•
69 56 56
150 163 170 164 166 155 160 159 172 172 149 158 162±2
53 64
1.49 1.70 1.80 1.59 1.64 1.54 1.60 1.67 1.72 1.66 1.49 1.63 1.63±0.03
Normal subjects F M M M M M M M M M F M
l
2 3 4 5 6 7 8 9 10 ll 12 Mean±SE COPD patients
M M M M M M M M
l
2 3 4 5 6 7 8 Mean±SE
68
55 61 64 77
60 64 55 57 62±2 63 63 62 70 73 77
66 55 66±3
172 167 159 164 160 157 156 165 163±2
*p
68
54 57 55 57 64 60 55 54 61 58±1 55 51 55 49 51 45
55 55 52±1*
1.66 1.58 1.57 1.53 1.53 1.43 1.55 1.61 1.56±0.02
from complaints referrable to cardiac, pulmonary. or neuromuscular systems, and also had normal physical examinations. Written informed consent was obtained from each subject before the start of the experiment. The anthropometric data of the two groups are shown in Table 1. Body surface area was calculated by using the formulas of Steven et al. 12 The mean values of age. height, and body surface area did not significantly differ among the groups. but the weight of the COPD group was significantly lower than that of the normal subjects (p < 0.01).
Pulmonary Function Tests The vital capacity and FEV 1 were obtained with a BenedictRoth spirometer. The pulmonary resistance (Rl) and static lung compliance (Cst) were measured in a pressure-compensated volume displacement body plethysmograph using an esophageal balloon. 13 Total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV) were determined by the gas dilution method. •• Carbon monoxide diffusion capacity was measured by the single-breath method. 15 The predicted normal values of Cotes 18 were used. Arterial blood gas tensions and pH were measured with a pH-blood gas analyzer (Instrumentation Laboratories 1302. Lexington, Mass) . The maximum static inspiratory (Pimax) and expiratory pressures (PEmax) were measured as the maximal inspiratory mouth pressure at RV and as the maximal expiratory mouth pressure at TLC,t 7 respectively.
Oxygen Consumption by Respiraton1 Muscles and Mouth Occlusion Pressure at 0.1 s of Inspiration In both patients and normal subjects, pulmonary function tests were performed first , followed by measurement of Vo2 of the respiratory muscles (Vo 2resp) on a separate day but within I week. Figure 1 shows a block diagram of the experimental setup. The apparatus consisted of a PO. l measurement circuit, an expandable dead space section, and an Vo2 measurement part.
Magnetic
Soda lime analyzer Fcoz.FOz
~----~11 '~--------------~ Measurement Expandable Oxygen Consumption
Ptl
Circuit
Dead Space Measurement
FIGURE I. Diagram of the apparatus. The expandable dead space tube was made from corrugated plastic tubing and was pulled and expanded at approximately 100 mVmin . The gas analyzer measured end-tidal CO, and 0,. and the measured gas was returned to the circuit. The magnetic valve in the small circuit was used to occlude the inspiratory flow to measure PO.l. The Vo 2tot was measured by a 9-L Collins spirometer. Vm. mouth flow; Pm. mouth pressure. CHEST I 105 I 3 I MARCH, 1994
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The P0.1 measurement circuit was as follows: a low dead space, two-way valve (model 1900: Hans Rudolph, Kansas City, Mo) was attached to the mouthpiece. A magnetic valve for occlusion was connected to the inspiratory side. Mouth pressure was measured at the mouthpiece using a pressure transducer (Validyne MP45, ±50 em H 20). Mouth pressure 0.1 s after onset of an occluded inspiration (P0.1) was measured with a system previously reported.'" Occlusion of the magnetic valve was controlled manually by a logic circuit, and was occluded randomly once every two to five breaths. The onsets of inspiration and expiration were detected electronically by changes in mouth pressure . Occlusion was induced during the preceding expiration to ensure that the inspiratory airway was completely occluded at the onset of inspiration. The valve was automatically opened after the first 120 ms of occluded inspiration. This detour circuit for P0.1 measurement was connected to a Fleisch pneumotachometer (No. 4) and three-way valve, then to the expandable dead space and devices for Vo 2 measurement. Except for the P0.1 measurement circuit, the systems were basically the same as in our previously reported apparatus.' Briefly, the expandable dead space section was made of a long piece of corrugated plastic tubing which had external and internal diameters of 4.0 and 3.3 em, respectively. To facilitate convenient control of the tube's length, it was laid in a 6-cm wide groove along a circular arc with a 65-cm radius. One end of the tube was connected to the P0.1 measurement circuit just described. The other end, free to move, was pulled along the groove at a constant rate. This rate was adjustable but, for the purpose of this study, was fixed at a rate corresponding to approximately 100 ml!min. The minimum volume of this dead space (corrugations fully compressed) was 1.0 L, and the maximum volume (fully extended) was 3.0 L. The total dead space ranged from 1.38 L to more than 3.0 L. The resistance of the combined system varied from 0.89 em H 20/Us in the minimal dead space configuration to 1.05 em H 20/Us in the maximal. The movable end of this expiratory dead space was connected to the Vo 2 measuring system. The Vo2 tot was measured by the decrease in volume of a 9-L Collins spirometer, initially filled with 100 percent oxygen, and connected to the movable end of the expanding dead space by a pair of flexible tubes. Circulating flow from the spirometer to the termination of the dead space through the pair of tubes was provided by a 40 Umin fan in one arm . Asoda lime box was placed in the other arm to absorb C0 2 . This arrangement effectively provides a constant gas composition of 100 percent 0 2 at the termination of the dead space. The spirometer was refilled with oxygen as necessary. The absence of outward air leakage through the system was confirmed by putting a 400-g weight on the bell of the spirometer, and the rate of dead space increase was also checked spirometrically before every Vo,tot measurement. Tidal volume was obtained by electrically integrating the flow signals (mouth flow) from the pneumotachometer and a pressure transducer (Validyne MP45, ± 5 em H 20). Minute ventilation was construed as 12 times the expired volume accumulated every 5 s. End-tidal C0 2 fraction (FETC0 2) and 0 2 fraction were continuously monitored at the mouthpiece with a rapidly responding infrared C0 2 analyzer and polarographic 0 2 electrode (model IH26; San-Ei Co, Tokyo, Japan). Gas was sampled at 20 ml!min and then returned to the circuit. The mouth flow, VE, Fco 2 , Fo 2 , P0.1, and the sum of rib cage and abdominal displacement were recorded on an eight-channel hot-pen recorder (RECTI-HORIZ 8K, San-Ei, Japan). Measurements were taken while the subjects were in a sitting position, and the rib cage and abdomen were fitted with belts of an inductance plethysmograph (Respitrace, Ardsley, NY). At first, the three-way valve between the pneumotachometer and dead space tube was opened to the atmosphere, and the subject
792
was asked to breathe air for a few minutes. The subjects also were asked to maintain their control (ie, off the mouthpiece) FRC by matching their rib cage and abdominal displacement signals at end-expiration to the isovolume FRC control line on the oscilloscope (Tektronix, 5130N) . The three-way valve was then turned, connecting the subject to the expandable dead space and Vo2 measurement devices. The expandable dead space was held at minimal volume for 3 min to allow the subject to reach a quasi-steady state at the initial dead space load of 1.38 L, after which it was increased at about 100 mllmin. The subjects were not allowed to observe the dead space expansion. Each subject breathed continuously with this increasing dead space until he could tolerate it no longe r. This point was signaled by the subject raising a hand, and the procedure was halted.
Data Analysis Total oxygen consumption (Vo 2 tot , milliliters per minute, standard conditions: temperature 0°C, pressure 760 mm Hg, and dry [0 water vapor]) was calculated as the 1-min decrease in spirometer volume minus the increase in dead space. In the present study, we assumed that metabolic Vo 2 (Vo 2 met) was constant during the measurement of \ 'o,. and defined Vo 2 tot as the summation of \'o,met and Vo 2 resp (ie, Vo 2tot = Vo 2 met + Vo 2resp). Therefore, the increment of Vo 2tot would reflect the increment ofVo,resp. The paired points ofVo., and VE were obtained every min~te or 30 s for a total of 5 o~ more and plotted on the semilog chart. Since the logarithm of Vo2 was found to be approximately linearly related to Vt:.' we characterized the Vo2 resp by the slope and the intercept (Vo,met) at VE = 0 of the semilog regression line . Linear regression analysis was performed by the least squares method. The slope of each regression line was expressed as ~log\'o,tot/~ VE, representing the following calculation [logVo,tot(2) - logVo 2 tot( l) ]/[V E(2) - VE( l)] at the arbitrary points of l and 2 during this measurement. Statistical analysis was performed by analysis of variance and Student's t test. Significance was accepted at a probability value of less than 0.05. All data are expressed as means± SE.
Table 2-Pulmonary Functions and Blood Gas Tensions in Age-Matched Normal Subjects and Patients With Chronic Obatructice Pulmonary Diaeaae* Pulmonary Function Data Vital capacity, %predicted FEV,, predicted Rl, em H,Oills Cst, Ucm H 20 TLC,% predicted FRC,% predicted RY, % predicted CO, diffusing capacity, %predicted Arterial blood pH PaO,, mm Hg PaC01 , mm Hg Plmax, em H.O PEmax, em H,O
Normal Subjects 102±4
COPD Patients 78±8t
101±6 2.1±0.2 0.25±0.01 103±4 102±5 102±5 100± 11
41±6:1: 9.1 ± 1.3§ 0.31±0.03 123±6t 129±7§ 183±9:1: 81±5
7.42±0.01 85.7±1.4 37.6±1.6 93±4 141±8
7.43±0.02 72.1±2.7:1: 39.3±2.6 60± 10§ 104±9§
*Values are means± SE. tp<0.05, compared with normal subjects. :J;p
A
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Fi<:l ' lll·: :2. E\amplt·s of aetna! tracings of \<>,tot. tracing was ohtailll'd frmn a normal snhjel'l I :\o. lm\'l'r tracing fron1 a patit•nt with COI'D ( -.:o. 71 . fin<" lint·s shtm· changt•s of t'\pandahlt• dt ·ad spact·. n•cordl'd IH"fon· nll·asun·nH ·nt of \i>,tot.
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1000 900 800 700 600 500 400 300
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lh:sn:rs The pulmonary function data are s11mmarized in Table 2. The percentage of FE\' 1 and R1 in COPD patients were significantly lower and significantly higher. respectin·ly . than the Yal11es in normal subjects. Furtlwnnore. the percentage of TLC , percentage of FHC. and percentage of HV of COPD patients were higher than those of normal s11bjects . Moderate h~11oxemia was seen in the COPD patients . Both P1max and PEmax of COPD patients were significantly lower than those of normal subjects (p < 0 .01). Ve 11/i Ia lio 11 a 11 d H£•.sp ira I o ry Oxy ge 11 Co IISI/IIl pt ion
Figure 2 shows examples of the actual traces of a normal subject and a patient with COPD . The fine lint:> on the charts indicatt:>s tlw dead space increnwnt condition. which was recorded before the nwasurement of each subject's \'o, . These traces re\·ealed that the distance. between- end-expiratory k,·el and tht:> fine line increased faster in the COPD patient . which means a higher rate of \ 'o, during dead space loading. compared with a nort~lal subject. Figure :3A shows the relationships between \ 'o}ot
100+---~---.---.---.~--.---.
0
10
20
30
40
50
60
'VE (L/min) FI
and \ 1E of the same subjects shown in Figure 2, which are plotted in a linear plot. If we replot the \lo 2tot and \IE on a semilog scale as shown in Figure .38, we can obtain the linear relationship between logVo 2tot and \'E. For example, this linear regression line of the same patient with COPD was obtained as logVo,tot = 2.11 + 0.0208 x \IE (r = 0.97), and that of the- normal subject was obtained as logVo,tot = 2. 16 + 0 .0091 X\'~-: (r = 0.96) as shown in Fig~tre :3. Relationships between log\'o,tot and \'E in all subjects were significant (p < O.Of) . and the mean correlation coefficient of all regression lines was r = 0 .98 ± 0 .02 in normal subjects and r = 0.9:3 ± 0 .01 in the COPD patients . Figure 4 shows scattered plots of each subject's CHEST I 105 I 3 I MARCH, 1994
793
p
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p
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0.51
o.4 0.3
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12
Elder Young Normal Normal Subjects Subjects
COPD
FIGURE 4. Comparison of .<1.logVo 2 toV.<1.VE between patients with COPD and young and elderly normal subjects. The mean alogVo2toV.<1.VE of COPD patients was significantly higher than that of both normal subjects (p < 0.001). The data of young normal subjects (age, 20 to 29 years) were taken from the previous article. 7 Bars indicate means± SE.
values of ~logVo 2toti~VE and mean values in both groups and in young normal subjects (20 to 29 years old), the data of which were taken from our previous article. 7 The mean value of ~logVo2toti~VE in COPD patients was significantly higher than that of elderly normal subjects and young normal subjects. The difference of ~logVo 2toti~VE between elderly and younger normal subjects also was significant. The ~logVo 2toti~VE of COPD patients was 2.8 times higher than that of elderly normal subjects, which was 1.6 times higher than that of young normal subjects. However, the mean Y-intercept of regression lines (Vo 2 met) in the COPD group (134.4 ± 10.9 mVmin) was not significantly different from that of elderly normal subjects (134.5 ± 9.9).
Ventilatory Changes During Oxygen Consumption Measurements Figure 5 shows the mean changes of tidal volume, respiratory frequency, VE, duty ratio of inspiration in a breathing cycle, P0.1 and FETC02 of normal 794
Tltnot
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~
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0 .....-,;..,~,-;~~~3!:---'•'--'5--~6--~7,--~8--~9--...:'10-::---'ll
O:,ad space increase
(min)
FIGURE SA. Mean changes of tidal volume (VT), respiratory frequency (0, and VE during dead space loading. B. Mean changes of inspiratory time ratio (Ti!ftot), PO.l, and FETC0 2 during dead space loading. Open circles indicate normal subjects and solid circles indicate patients with COPD. Bars indicate SE. Comparisons were tested at corresponding times in two groups. Asterisk, p < 0.05; double asterisks, p < 0.01.
subjects and patients with COPD during the measurements of Vo 2resp. The mean duration of dead space loading in COPD patients (8.1 ± 0.7 min) was significantly shorter than that in normal subjects (11.4 ± 1.0 min, p < 0.05). The VE values at rest and at 1 min after dead space loading in COPD patients were higher than those of normal subjects, and VE from 2 min after dead space loading did not differ from the corresponding values in normal subjects. The tidal volume of COPD patients did not differ significantly from that of normal subjects, but that from 2 min after dead space loading tended to be less than the corresponding values of normal subjects. The respiratory frequency of COPD patients Oxygen Consumption of Respiratory Muscles in COPD Patients (Shindoh at a/)
was significantly higher than the corresponding values of normal subjects. The duty ratio of inspiration in a breathing cycle was not different between the two groups . The P0.1 as an index of the respiratory drive ofCOPD patients was significantly higher than the corresponding P0.1 of normal subjects. The FETC0 2 of COPD patients was higher than that of normal subjects from 5 to 8 min after dead space loading. From these results , in COPD patients respiratory drive is greater than normal subjects during dead space loading.
Respiratory Oxygen Consumption and Mouth Occlusion Pressure at O.ls of Inspiration The logVo 2tot had a linear correlation with P0.1 in all subjects (p < 0.01) , and mean values of the slope (LllogVo 2tot/LlPO.l) obtained from linear regression lines were 0.034 ± 0.012 and 0.029 ± 0.010 (log[ml!min]/cm Hp) in COPD patients and normal subjects, respectively. These values were not different between the two groups. The mean intercepts of Y axis were 149.6 ± 12.8 and 152.3 ± 8.8 ml!min in COPD patients and normal subjects, respectively. These values also were not different between the two groups. DISCUSSION
In the present study, we found that the LllogVo 2totl LlVE in patients with COPD was significantly higher than in age-matched normal subjects. However, Vo 2 met did not differ significntly between the two groups. If in the present study we assume that Vo 2 met reflects metabolic oxygen consumption exclusive of the respiratory muscles and is constant during measurement of Vo 2 , increase in Vo 2tot may reflect the increase in Vo 2 resp. Therefore, the differences given by LllogVo 2totlLlVE might indicate the differences in the Vo 2 resp.
Methodologic Considerations In the present study, the P0.1 values of normal subjects were sufficiently consistent with the previous study,N and those of COPD patients at rest were significantly higher than those of normal subjects. There are other possibilities besides respiratory drive which affect P0.1. The first possibility is a change in lung volume. The percentage of FRC of COPD patients was significantly higher compared with that in normal subjects, and this may flatten the diaphragm, resulting in a decrease in PO.l. Furthermore, COPD patients increase FRC with an increase in VE. Therefore, the higher value of P0.1 in COPD patients not only at rest but also during dead space loading may be rather underestimated. During dead space loading, we asked subjects to maintain constant FRC as soon as possible. Thus,
we believe that the effects of lung volume change on P0.1 are negligible. The second possibility is that the shape of the curve representing mouth pressure may change during hyperpnea. It has been reported that COPD patients show a more convex curve during exercise.19 If the shape of this curve became more convex during dead space loading, P0.1 would be overestimated. The third possibility is that high impedance in COPD might affect PO.l. When there is a large inequality of the time constants in the lungs, the thorax at the moment of occlusion may have a small passive pressure change of "intrinsic positive endexpiratory pressure." Therefore, P0.1 may not reflect the beginning of negative pleural pressure as the output of the respiratory controller. This effect may be greater with an increase in VE. Unfortunately, these possibilities in COPD patients were not eliminated in the present study. The FETC0 2 in the COPD patients tended to be higher than that of normal subjects during dead space loading. It is suggested that the accumulation of C0 2 may affect the measurement of Vo 2resp. Even if we measured Vo 2tot at every minute, the changes in FETC02 of COPD patients were recognized as slightly increased at every minute, as shown in Figure 5B. In the previous study,i we suggested that the underestimation of Vo 2tot due to C0 2 accumulation of the closed system would be less than 2.0 percent in young normal subjects. However, in the present study, the FETC0 2 of COPD patients was 3.5 percent to total external dead space 2.14 L, and that of age-matched normal subjects was 2.3 percent to total external dead space 2.44 L. Consequently, we speculated that the underestimation of Vo 2 tot may be larger than that of agematched normal subjects, but we could not eliminate this underestimation due to methodologic limitations. Ventilatory change from rest to the end of dead space loading seemed to be less in COPD patients than in normal subjects. In addition, the COPD patient increased tidal volume less than that of normal subjects; hence, the ratio of physiologic dead space volume to tidal volume in COPD patients seems to be greater than that of normal subjects for a given dead space. These two mechanisms are suggested to contribute to the larger increase of FETC0 2 in COPD patients.
Comparison With Previous Studies Previous studies3.4.6 have shown that Vo 2resp in patients with COPD is much greater than that in young normal subjects. Cherniacl2 reported that the mean oxygen cost was 1.16 milL ventilation in 16 normal subjects (21 to 43 years), while it was 5.96 CHEST I 105 I 3 I MARCH, 1994
795
mVL ventilation in 22 older emphysematous subjects (47 to 73 years). McGregor and Becklake4 reported that the Vo2 resp was 4.9 to 65.7 mVmin in three older patients with emphysema (49 to 66 years) but was 1.3 to 5.5 mVmin in five normal subjects (28 to 44 years). Furthermore, Campbell et al6 reported results in a 59-year-old patient with emphysema that were similar to those of a 31-yearold normal subject. However, these previous studies did not compare the Vo 2 resp between COPD patients and normal subjects in the same age range. Because we found in our previous study that 4logVo 2 tot/.1VE increased significantly with age/ Vo2resp in patients with COPD should be compared with that of normal subjects in the same age range. Based upon these studies, we measured the Vo 2 resp in COPD patients and normal subjects in the same age range, and our results confirmed that there is a significant difference of approximately 2.8 times higher mean Vo 2 resp at any VE in COPD patients than in age-matched normal subjects (Fig 4). If we could eliminate the aging effect on Vo2 resp of COPD patients, we may conclude that the observed increment of Vo 2resp in the COPD patients is caused by pathophysiologic factors.
Possible Mechanisms in Increment of Respiratory Muscle Oxygen Consumption In the COPD patients, the values of .1logVo2totl .1VE had wider variability than those of elderly and young normal subjects, as shown in Figure 4. There might be several mechanisms that contribute to the increment of .1logVo2tot/.1VE in the COPD patients. The first possibility may be that the differences between lung function at rest breathing resulted in the differences during the dead space loading. The Vo 2 resp might be closely related to mechanical impedance of the respiratory system, which is determined by resistance, compliance, and inertia of the lung and chest wall. We speculate that an increase in airway resistance and a decrease in lung compliance would increase the resistive and elastic work of the respiratory muscles, respectively. In the present study, the Cst in the COPD patients was not significantly different from that in normal subjects. Therefore, the remarkably increased R1 in COPD seems to contribute to increase the overall impedance of the respiratory system and may contribute to an increase in the Vo2 resp. Recent studies have shown that hyperinflation of the lung increases the Vo 2 resp in normal subjects. Collett and Engel 20 reported that when normal subjects increased FRC to 37 percent of inspiratory capacity, the oxygen cost of breathing was significantly increased by 41 percent, from 109 mVmin at FRC. McCool et al 21 also reported the same effect 796
on the oxygen cost of breathing. They speculated that this increment in oxygen cost may be due to changes in mechanical coupling in the pattern of recruitment of the respiratory muscles or changes in the intrinsic properties of the inspiratory muscles at shorter length (ie, at higher lung volume). Although we recognized a significantly greater percentage of FRC in patients with COPD than in normal subjects, the increment in Vo2 resp during dead space loading could not be explained by the change in FRC because we maintained the initial FRC constant during the measurement. The malnutrition in patients with COPD may be associated with the increment in Vo2 resp. Arora and Rochester2 reported that poorly nourished patients had reduced P1max and PEmax and maximal voluntary ventilation. Furthermore, Donahoe et al 23 reported that 0 2 cost was significantly elevated in malnourished patients with COPD (4.28 ml 0/L ventilation) relative to a normally nourished group (2.61 ml 0/L ventilation), and the measured resting energy expenditure also was increased compared with predicted values for the normally nourished population. These reports suggest that malnutrition seems to adversely influence respiratory muscle strength, and the combination of increased 0 2 cost and reduced muscle strength could be presented in the COPD patients. In the present study, the mean weight of the COPD group was significantly lower compared with that of normal subjects (p < 0.01), and both P1max and PEmax of COPD patients were significantly reduced (Table 2). It is difficult to determine the cause; however, we may suggest that the increase ofVo2 resp might be influenced by body weight and muscle strength in the COPD patients. The present study showed that Vo 2tot increases are associated with an increase in P0.1 in COPD patients and normal subjects and that Vo 2tot at a given P0.1 was the same between both groups. These suggest that respiratory Vo 2 has a good correlation with the output of the respiratory controller. Perhaps an increase in neural activity of the respiratory controller would cause an increase of respiratory muscle contraction, resulting in an increase in respiratory Vo 2 • In conclusion, COPD patients showed significantly higher Vo2 resp than that caused by the aging effect of normal subjects. This increase might be related to the total effect of deterioration of lung function and respiratory drive. ACKNOWLEDGMENT: We gratefully acknowledge the assistance of Mr. B. Bell in the preparation of this manuscript.
REFERENCES 1 Coumand A, Richards DW, Bader RA , Bader ME, Fishman AP. The oxygen cost of breathing. Trans Assoc Am Physicians 1954; 67:662-73 Oxygen Consumption of Respiratory Muscles in COPD Patients (Shindoh
et al)
2 Fritts HW Jr. Filler J. Fishman AP, Coumand A. The efficiency of ventilation during voluntary hyperpnea: studies in normal subjects and in dyspneic with either chronic pulmonary emphysema or obesity. JClin Invest 1959; 38:1339-
14
41l
3 Cherniack RM. The oxygen consumption and efficiency of the respiratory muscles in health and emphysema. J Clin Invest 1959; 38:494-99 4 McGregor M, Becklake MR. The relationship of oxygen cost of breathing to respiratory mechanical work and respiratory force. J Clin Invest 1961; 40:971-80 5 McKerrow CB, Otis AB. Oxygen cost of hyperventilation. J Appl Physiol 1956; 9:375-79 6 Campbell EJM, Westlake EK, Cherniack RM. Simple methods of estimating oxygen consumption and efficiency of the muscles of breathing. J Appl Physiol 1957; 11:303-08 7 Takishima T , Shindoh C , Kikuchi Y, Hida W, Inoue H. Aging effect on oxygen consumption of respiratory muscles in humans . J Appl Physiol 1990; 69:14-20 8 Whitelaw WA, Derenne JP. Milic-Emili J. Occlusion pressure as a measure of respiratory center output in conscious man . Resp Physiol 1975: 23:181-99 9 Altose MD, McCauley WC, Kelsen SC, Cherniack NS . Effects of hypercapnia and inspiratory flow-resistive loading on respiratory activity in chronic airways obstruction. J Clin Invest 1977; 59:500-07 10 Fales JT. Heisey SR. Zierler KL. Dependency of oxygen consumption of skeletal muscle on number of stimuli during work in the dog. Am J Physiol 1960; 198:1333-42 11 American Thoracic Society. Chronic bronchitis, asthma, and pulmonary emphysema. Am Rev Respir Dis 1962; 85:762-68 12 Steven AC, Kinasewitz CT, George RB. Pulmonary function testing. New York: Churchill Livingstone, 1984; 335-53 13 Macklem PT. Leith DE , Mead J. Procedures for standardized measurements of lung mechanics. Bethesda, Md: Na-
15
16 17 18
19
20 21 22 23
tiona! Heart and Lung Institute, Division of Lung Diseases, 1974 Rodenstein DO, Stanescu DC. Reassessment of lung volume measurement by helium dilution and by body plethysmography In chronic air-flow obstruction. Am Rev Respir Dis 1982; 126:1040-44 Ogilvie CM, Forster RE, Blakemore WA, Morton JW. A standardized breath holding technique for the clinical measurement of the diffusing capacity of the lung for carbon monoxide. J Clin Invest 1957; 36:1-17 Cotes JE. Lung function. 4th ed. Oxford, England: Blackwell Scientific Publication, 1979; 365-87 Rochester DF, Braun NM . Determinants of maximal inspiratory pressure in chronic obstructive pulmonary disease. Am Rev Respir Dis 1985; 132:42-7 Hida W, Suzuki R, Kikuchi Y, Shindoh C, Chonan T, Sasaki H, et al. Effect of local vibration on ventilatory response to hypercapnia in normal subjects. Bull Eur Physiopath Resp 1987; 23:227-32 Sergysels R, van Meerhaeghe A, Scano C, Denaut M, Willeput R, Messin R, et al. Respiratory drive during exercise in chronic obstructive lung disease. Bull Eur Physiopath Resp 1981; 17:755-66 Collett PW, Engel LA. Influence of lung volume on oxygen cost of resistive breathing. J Appl Physiol 1986; 61 :16-24 McCool FD, Tzelepis CE, Leith DE, Hoppin FG. Oxygen cost of breathing during fatiguing inspiratory resistive loads. J Appl Physiol 1989; 66:2045-55 Arora NS, Rochester DF. Respiratory muscle strength and maximal voluntary ventilation in undernourished patients. Am Rev Respir Dis 1982; 126:5-8 Donahoe M, Rogers RM, Wilson DO, Pennock BE. Oxygen consumption of the respiratory muscles in normal and in malnourished patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1989; 140:385-91
CHEST I 105 I 3 I MARCH, 1994
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subjects at the corresponding dead space loading. However, the ""E did not differ between the two groups except for at rest and the first 1 min after dead space loading. These results suggest that the 2 of respiratory muscles in patients with COPD is higher at given ventilation compared with that in age-matched normal subjects and that this increased ""o 2 partly may be due to an augmented ventilatory drive. (Cheat 1994; 105: 790-97)
previous studies 1· 6 have shown that the oxygen cost of respiratory muscles in patients with COPD increases more than that of normal subjects when they increase minute ventilation (VE). However, in most studies, oxygen consumption (Vo 2 ) of respiratory muscles has been measured in patients with COPD whose ages ranged from 44 to 72 years and in normal subjects, for the most part, from 19 to 47 years of age. Because most of the patients with COPD are relatively elderly subjects and because we have recently found that the Vo 2 of respiratory muscles increases with aging in normal subjects/ we should compare the respiratory Vo 2 in patients with COPD with that of normal subjects who are in an age-matched group. In our previous study/ VE was used as a parameter of respiratory muscle task, and the slope of the regression line between logarithm of total Vo 2 (logVo 2tot) and VE (~logVo 2 toti~VE) expressed the overall respiratory muscle efficiency. However, because the VE in patients with COPD is generally restricted by airflow obstruction, the ratio
(~logVo 2 toti~VE) may possibly be higher than that in normal subjects. Mouth occlusion pressure (PO.l)H has been widely used as the output of the respiratory controller not only in normal subjects, but also in COPD patients. 9 Fales et al 10 also reported that Vo 2 in skeletal muscle changed according to stimulation frequencies . Since an increase in stimulation frequency is caused by an increase in respiratory drive, our hypothesis is that the energy cost of muscle contraction may increase with an associated increase in respiratory drive. In the present study, we measured total Vo 2 (Vo 2tot), VE, PO.l, and other ventilatory variables during continuously expandable dead space loading in patients with COPD and age-matched normal subjects.
""0
*From the First Department of Internal Medicine, Tohoku University School ofMedicine, Sendai, Japan. This worl< was supported by the Grant-in-Aid for Developmental Scientific Research (No. 01870037) of the Ministry of Education, Science and Culture, Japan. Manuscript received November 24, 1992; revision accepted July I, 1993. Reprint requests: Dr. Shirato, 1st Department of Internal Medicine, Tohoku University, 1-1 Seiryo machi, Aoha-ku, Sendai 980, Japan
790
""0
Cst= static lung compliance; FETC01 =end-tidal C01 fraction; FRC = funCtional residual capacity; log'(To1tur= logBrithm of total oxygen consumption; P(f.I = mouth occlusion pres· sure at 0.1 s of inspiration; PEmax = maximum static expiratory pressure; Punax = maximum static inspiratory _pressure; Rl ., fulmonary resistance; RV = res1dual vofume; TLC '" tota lung capacity; ~E = minute ventilation; '(To~ = metaboliC oxygen consumption; ~o1 res = respiratory muscle oxygen consumption; ~o1 lol = toial oxygen consumption
METHODS
Subjects We studied 8 patients with COPD (66 ± 3 years) and 12 elderly normal subjects (62 ± 2 years) . The patients with COPD were diagnosed by clinical symptoms, chest roentgenographic findings, and lung function data, and the diagnoses of pulmonary emphysema and chronic bronchitis were consistent with the diagnostic standards of the American Thoracic Society." All patients with COPD were in a stable clinical state and had shown no substantial changes in pulmonary function during the previous 6 months. Bronchodilator usage was withheld for at least 16 h before the experiments. Normal subjects, who were selected from a group of active workers or ex-workers (> 63 years) of an electric company with the company's coordination , and did not know about the aim of the present study, were free Oxygen Consumption of Respiratory Muscles in COPD Patients (Shindoh et at)
Table 1-Anthropometric Charocterinica of Age-Matched Normal Subject. and Chronic Olmrvctioe Pulmona'll lJi3eaae lbtienl3 Body Subject No.
Sex
Age, yr
Height, em
Weight, kg
Surface Area, m•
69 56 56
150 163 170 164 166 155 160 159 172 172 149 158 162±2
53 64
1.49 1.70 1.80 1.59 1.64 1.54 1.60 1.67 1.72 1.66 1.49 1.63 1.63±0.03
Normal subjects F M M M M M M M M M F M
l
2 3 4 5 6 7 8 9 10 ll 12 Mean±SE COPD patients
M M M M M M M M
l
2 3 4 5 6 7 8 Mean±SE
68
55 61 64 77
60 64 55 57 62±2 63 63 62 70 73 77
66 55 66±3
172 167 159 164 160 157 156 165 163±2
*p
68
54 57 55 57 64 60 55 54 61 58±1 55 51 55 49 51 45
55 55 52±1*
1.66 1.58 1.57 1.53 1.53 1.43 1.55 1.61 1.56±0.02
from complaints referrable to cardiac, pulmonary. or neuromuscular systems, and also had normal physical examinations. Written informed consent was obtained from each subject before the start of the experiment. The anthropometric data of the two groups are shown in Table 1. Body surface area was calculated by using the formulas of Steven et al. 12 The mean values of age. height, and body surface area did not significantly differ among the groups. but the weight of the COPD group was significantly lower than that of the normal subjects (p < 0.01).
Pulmonary Function Tests The vital capacity and FEV 1 were obtained with a BenedictRoth spirometer. The pulmonary resistance (Rl) and static lung compliance (Cst) were measured in a pressure-compensated volume displacement body plethysmograph using an esophageal balloon. 13 Total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV) were determined by the gas dilution method. •• Carbon monoxide diffusion capacity was measured by the single-breath method. 15 The predicted normal values of Cotes 18 were used. Arterial blood gas tensions and pH were measured with a pH-blood gas analyzer (Instrumentation Laboratories 1302. Lexington, Mass) . The maximum static inspiratory (Pimax) and expiratory pressures (PEmax) were measured as the maximal inspiratory mouth pressure at RV and as the maximal expiratory mouth pressure at TLC,t 7 respectively.
Oxygen Consumption by Respiraton1 Muscles and Mouth Occlusion Pressure at 0.1 s of Inspiration In both patients and normal subjects, pulmonary function tests were performed first , followed by measurement of Vo2 of the respiratory muscles (Vo 2resp) on a separate day but within I week. Figure 1 shows a block diagram of the experimental setup. The apparatus consisted of a PO. l measurement circuit, an expandable dead space section, and an Vo2 measurement part.
Magnetic
Soda lime analyzer Fcoz.FOz
~----~11 '~--------------~ Measurement Expandable Oxygen Consumption
Ptl
Circuit
Dead Space Measurement
FIGURE I. Diagram of the apparatus. The expandable dead space tube was made from corrugated plastic tubing and was pulled and expanded at approximately 100 mVmin . The gas analyzer measured end-tidal CO, and 0,. and the measured gas was returned to the circuit. The magnetic valve in the small circuit was used to occlude the inspiratory flow to measure PO.l. The Vo 2tot was measured by a 9-L Collins spirometer. Vm. mouth flow; Pm. mouth pressure. CHEST I 105 I 3 I MARCH, 1994
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The P0.1 measurement circuit was as follows: a low dead space, two-way valve (model 1900: Hans Rudolph, Kansas City, Mo) was attached to the mouthpiece. A magnetic valve for occlusion was connected to the inspiratory side. Mouth pressure was measured at the mouthpiece using a pressure transducer (Validyne MP45, ±50 em H 20). Mouth pressure 0.1 s after onset of an occluded inspiration (P0.1) was measured with a system previously reported.'" Occlusion of the magnetic valve was controlled manually by a logic circuit, and was occluded randomly once every two to five breaths. The onsets of inspiration and expiration were detected electronically by changes in mouth pressure . Occlusion was induced during the preceding expiration to ensure that the inspiratory airway was completely occluded at the onset of inspiration. The valve was automatically opened after the first 120 ms of occluded inspiration. This detour circuit for P0.1 measurement was connected to a Fleisch pneumotachometer (No. 4) and three-way valve, then to the expandable dead space and devices for Vo 2 measurement. Except for the P0.1 measurement circuit, the systems were basically the same as in our previously reported apparatus.' Briefly, the expandable dead space section was made of a long piece of corrugated plastic tubing which had external and internal diameters of 4.0 and 3.3 em, respectively. To facilitate convenient control of the tube's length, it was laid in a 6-cm wide groove along a circular arc with a 65-cm radius. One end of the tube was connected to the P0.1 measurement circuit just described. The other end, free to move, was pulled along the groove at a constant rate. This rate was adjustable but, for the purpose of this study, was fixed at a rate corresponding to approximately 100 ml!min. The minimum volume of this dead space (corrugations fully compressed) was 1.0 L, and the maximum volume (fully extended) was 3.0 L. The total dead space ranged from 1.38 L to more than 3.0 L. The resistance of the combined system varied from 0.89 em H 20/Us in the minimal dead space configuration to 1.05 em H 20/Us in the maximal. The movable end of this expiratory dead space was connected to the Vo 2 measuring system. The Vo2 tot was measured by the decrease in volume of a 9-L Collins spirometer, initially filled with 100 percent oxygen, and connected to the movable end of the expanding dead space by a pair of flexible tubes. Circulating flow from the spirometer to the termination of the dead space through the pair of tubes was provided by a 40 Umin fan in one arm . Asoda lime box was placed in the other arm to absorb C0 2 . This arrangement effectively provides a constant gas composition of 100 percent 0 2 at the termination of the dead space. The spirometer was refilled with oxygen as necessary. The absence of outward air leakage through the system was confirmed by putting a 400-g weight on the bell of the spirometer, and the rate of dead space increase was also checked spirometrically before every Vo,tot measurement. Tidal volume was obtained by electrically integrating the flow signals (mouth flow) from the pneumotachometer and a pressure transducer (Validyne MP45, ± 5 em H 20). Minute ventilation was construed as 12 times the expired volume accumulated every 5 s. End-tidal C0 2 fraction (FETC0 2) and 0 2 fraction were continuously monitored at the mouthpiece with a rapidly responding infrared C0 2 analyzer and polarographic 0 2 electrode (model IH26; San-Ei Co, Tokyo, Japan). Gas was sampled at 20 ml!min and then returned to the circuit. The mouth flow, VE, Fco 2 , Fo 2 , P0.1, and the sum of rib cage and abdominal displacement were recorded on an eight-channel hot-pen recorder (RECTI-HORIZ 8K, San-Ei, Japan). Measurements were taken while the subjects were in a sitting position, and the rib cage and abdomen were fitted with belts of an inductance plethysmograph (Respitrace, Ardsley, NY). At first, the three-way valve between the pneumotachometer and dead space tube was opened to the atmosphere, and the subject
792
was asked to breathe air for a few minutes. The subjects also were asked to maintain their control (ie, off the mouthpiece) FRC by matching their rib cage and abdominal displacement signals at end-expiration to the isovolume FRC control line on the oscilloscope (Tektronix, 5130N) . The three-way valve was then turned, connecting the subject to the expandable dead space and Vo2 measurement devices. The expandable dead space was held at minimal volume for 3 min to allow the subject to reach a quasi-steady state at the initial dead space load of 1.38 L, after which it was increased at about 100 mllmin. The subjects were not allowed to observe the dead space expansion. Each subject breathed continuously with this increasing dead space until he could tolerate it no longe r. This point was signaled by the subject raising a hand, and the procedure was halted.
Data Analysis Total oxygen consumption (Vo 2 tot , milliliters per minute, standard conditions: temperature 0°C, pressure 760 mm Hg, and dry [0 water vapor]) was calculated as the 1-min decrease in spirometer volume minus the increase in dead space. In the present study, we assumed that metabolic Vo 2 (Vo 2 met) was constant during the measurement of \ 'o,. and defined Vo 2 tot as the summation of \'o,met and Vo 2 resp (ie, Vo 2tot = Vo 2 met + Vo 2resp). Therefore, the increment of Vo 2tot would reflect the increment ofVo,resp. The paired points ofVo., and VE were obtained every min~te or 30 s for a total of 5 o~ more and plotted on the semilog chart. Since the logarithm of Vo2 was found to be approximately linearly related to Vt:.' we characterized the Vo2 resp by the slope and the intercept (Vo,met) at VE = 0 of the semilog regression line . Linear regression analysis was performed by the least squares method. The slope of each regression line was expressed as ~log\'o,tot/~ VE, representing the following calculation [logVo,tot(2) - logVo 2 tot( l) ]/[V E(2) - VE( l)] at the arbitrary points of l and 2 during this measurement. Statistical analysis was performed by analysis of variance and Student's t test. Significance was accepted at a probability value of less than 0.05. All data are expressed as means± SE.
Table 2-Pulmonary Functions and Blood Gas Tensions in Age-Matched Normal Subjects and Patients With Chronic Obatructice Pulmonary Diaeaae* Pulmonary Function Data Vital capacity, %predicted FEV,, predicted Rl, em H,Oills Cst, Ucm H 20 TLC,% predicted FRC,% predicted RY, % predicted CO, diffusing capacity, %predicted Arterial blood pH PaO,, mm Hg PaC01 , mm Hg Plmax, em H.O PEmax, em H,O
Normal Subjects 102±4
COPD Patients 78±8t
101±6 2.1±0.2 0.25±0.01 103±4 102±5 102±5 100± 11
41±6:1: 9.1 ± 1.3§ 0.31±0.03 123±6t 129±7§ 183±9:1: 81±5
7.42±0.01 85.7±1.4 37.6±1.6 93±4 141±8
7.43±0.02 72.1±2.7:1: 39.3±2.6 60± 10§ 104±9§
*Values are means± SE. tp<0.05, compared with normal subjects. :J;p
A
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30
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.......
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Fi<:l ' lll·: :2. E\amplt·s of aetna! tracings of \<>,tot. tracing was ohtailll'd frmn a normal snhjel'l I :\o. lm\'l'r tracing fron1 a patit•nt with COI'D ( -.:o. 71 . fin<" lint·s shtm· changt•s of t'\pandahlt• dt ·ad spact·. n•cordl'd IH"fon· nll·asun·nH ·nt of \i>,tot.
The upper HI allll thl' Continuous which \\'l'rt'
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B
1000 900 800 700 600 500 400 300
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·>
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lh:sn:rs The pulmonary function data are s11mmarized in Table 2. The percentage of FE\' 1 and R1 in COPD patients were significantly lower and significantly higher. respectin·ly . than the Yal11es in normal subjects. Furtlwnnore. the percentage of TLC , percentage of FHC. and percentage of HV of COPD patients were higher than those of normal s11bjects . Moderate h~11oxemia was seen in the COPD patients . Both P1max and PEmax of COPD patients were significantly lower than those of normal subjects (p < 0 .01). Ve 11/i Ia lio 11 a 11 d H£•.sp ira I o ry Oxy ge 11 Co IISI/IIl pt ion
Figure 2 shows examples of the actual traces of a normal subject and a patient with COPD . The fine lint:> on the charts indicatt:>s tlw dead space increnwnt condition. which was recorded before the nwasurement of each subject's \'o, . These traces re\·ealed that the distance. between- end-expiratory k,·el and tht:> fine line increased faster in the COPD patient . which means a higher rate of \ 'o, during dead space loading. compared with a nort~lal subject. Figure :3A shows the relationships between \ 'o}ot
100+---~---.---.---.~--.---.
0
10
20
30
40
50
60
'VE (L/min) FI
and \ 1E of the same subjects shown in Figure 2, which are plotted in a linear plot. If we replot the \lo 2tot and \IE on a semilog scale as shown in Figure .38, we can obtain the linear relationship between logVo 2tot and \'E. For example, this linear regression line of the same patient with COPD was obtained as logVo,tot = 2.11 + 0.0208 x \IE (r = 0.97), and that of the- normal subject was obtained as logVo,tot = 2. 16 + 0 .0091 X\'~-: (r = 0.96) as shown in Fig~tre :3. Relationships between log\'o,tot and \'E in all subjects were significant (p < O.Of) . and the mean correlation coefficient of all regression lines was r = 0 .98 ± 0 .02 in normal subjects and r = 0.9:3 ± 0 .01 in the COPD patients . Figure 4 shows scattered plots of each subject's CHEST I 105 I 3 I MARCH, 1994
793
p
--
p
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p
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..., ...,0
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-
•
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0.51
o.4 0.3
15
12
Elder Young Normal Normal Subjects Subjects
COPD
FIGURE 4. Comparison of .<1.logVo 2 toV.<1.VE between patients with COPD and young and elderly normal subjects. The mean alogVo2toV.<1.VE of COPD patients was significantly higher than that of both normal subjects (p < 0.001). The data of young normal subjects (age, 20 to 29 years) were taken from the previous article. 7 Bars indicate means± SE.
values of ~logVo 2toti~VE and mean values in both groups and in young normal subjects (20 to 29 years old), the data of which were taken from our previous article. 7 The mean value of ~logVo2toti~VE in COPD patients was significantly higher than that of elderly normal subjects and young normal subjects. The difference of ~logVo 2toti~VE between elderly and younger normal subjects also was significant. The ~logVo 2toti~VE of COPD patients was 2.8 times higher than that of elderly normal subjects, which was 1.6 times higher than that of young normal subjects. However, the mean Y-intercept of regression lines (Vo 2 met) in the COPD group (134.4 ± 10.9 mVmin) was not significantly different from that of elderly normal subjects (134.5 ± 9.9).
Ventilatory Changes During Oxygen Consumption Measurements Figure 5 shows the mean changes of tidal volume, respiratory frequency, VE, duty ratio of inspiration in a breathing cycle, P0.1 and FETC02 of normal 794
Tltnot
I
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~
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0 .....-,;..,~,-;~~~3!:---'•'--'5--~6--~7,--~8--~9--...:'10-::---'ll
O:,ad space increase
(min)
FIGURE SA. Mean changes of tidal volume (VT), respiratory frequency (0, and VE during dead space loading. B. Mean changes of inspiratory time ratio (Ti!ftot), PO.l, and FETC0 2 during dead space loading. Open circles indicate normal subjects and solid circles indicate patients with COPD. Bars indicate SE. Comparisons were tested at corresponding times in two groups. Asterisk, p < 0.05; double asterisks, p < 0.01.
subjects and patients with COPD during the measurements of Vo 2resp. The mean duration of dead space loading in COPD patients (8.1 ± 0.7 min) was significantly shorter than that in normal subjects (11.4 ± 1.0 min, p < 0.05). The VE values at rest and at 1 min after dead space loading in COPD patients were higher than those of normal subjects, and VE from 2 min after dead space loading did not differ from the corresponding values in normal subjects. The tidal volume of COPD patients did not differ significantly from that of normal subjects, but that from 2 min after dead space loading tended to be less than the corresponding values of normal subjects. The respiratory frequency of COPD patients Oxygen Consumption of Respiratory Muscles in COPD Patients (Shindoh at a/)
was significantly higher than the corresponding values of normal subjects. The duty ratio of inspiration in a breathing cycle was not different between the two groups . The P0.1 as an index of the respiratory drive ofCOPD patients was significantly higher than the corresponding P0.1 of normal subjects. The FETC0 2 of COPD patients was higher than that of normal subjects from 5 to 8 min after dead space loading. From these results , in COPD patients respiratory drive is greater than normal subjects during dead space loading.
Respiratory Oxygen Consumption and Mouth Occlusion Pressure at O.ls of Inspiration The logVo 2tot had a linear correlation with P0.1 in all subjects (p < 0.01) , and mean values of the slope (LllogVo 2tot/LlPO.l) obtained from linear regression lines were 0.034 ± 0.012 and 0.029 ± 0.010 (log[ml!min]/cm Hp) in COPD patients and normal subjects, respectively. These values were not different between the two groups. The mean intercepts of Y axis were 149.6 ± 12.8 and 152.3 ± 8.8 ml!min in COPD patients and normal subjects, respectively. These values also were not different between the two groups. DISCUSSION
In the present study, we found that the LllogVo 2totl LlVE in patients with COPD was significantly higher than in age-matched normal subjects. However, Vo 2 met did not differ significntly between the two groups. If in the present study we assume that Vo 2 met reflects metabolic oxygen consumption exclusive of the respiratory muscles and is constant during measurement of Vo 2 , increase in Vo 2tot may reflect the increase in Vo 2 resp. Therefore, the differences given by LllogVo 2totlLlVE might indicate the differences in the Vo 2 resp.
Methodologic Considerations In the present study, the P0.1 values of normal subjects were sufficiently consistent with the previous study,N and those of COPD patients at rest were significantly higher than those of normal subjects. There are other possibilities besides respiratory drive which affect P0.1. The first possibility is a change in lung volume. The percentage of FRC of COPD patients was significantly higher compared with that in normal subjects, and this may flatten the diaphragm, resulting in a decrease in PO.l. Furthermore, COPD patients increase FRC with an increase in VE. Therefore, the higher value of P0.1 in COPD patients not only at rest but also during dead space loading may be rather underestimated. During dead space loading, we asked subjects to maintain constant FRC as soon as possible. Thus,
we believe that the effects of lung volume change on P0.1 are negligible. The second possibility is that the shape of the curve representing mouth pressure may change during hyperpnea. It has been reported that COPD patients show a more convex curve during exercise.19 If the shape of this curve became more convex during dead space loading, P0.1 would be overestimated. The third possibility is that high impedance in COPD might affect PO.l. When there is a large inequality of the time constants in the lungs, the thorax at the moment of occlusion may have a small passive pressure change of "intrinsic positive endexpiratory pressure." Therefore, P0.1 may not reflect the beginning of negative pleural pressure as the output of the respiratory controller. This effect may be greater with an increase in VE. Unfortunately, these possibilities in COPD patients were not eliminated in the present study. The FETC0 2 in the COPD patients tended to be higher than that of normal subjects during dead space loading. It is suggested that the accumulation of C0 2 may affect the measurement of Vo 2resp. Even if we measured Vo 2tot at every minute, the changes in FETC02 of COPD patients were recognized as slightly increased at every minute, as shown in Figure 5B. In the previous study,i we suggested that the underestimation of Vo 2tot due to C0 2 accumulation of the closed system would be less than 2.0 percent in young normal subjects. However, in the present study, the FETC0 2 of COPD patients was 3.5 percent to total external dead space 2.14 L, and that of age-matched normal subjects was 2.3 percent to total external dead space 2.44 L. Consequently, we speculated that the underestimation of Vo 2 tot may be larger than that of agematched normal subjects, but we could not eliminate this underestimation due to methodologic limitations. Ventilatory change from rest to the end of dead space loading seemed to be less in COPD patients than in normal subjects. In addition, the COPD patient increased tidal volume less than that of normal subjects; hence, the ratio of physiologic dead space volume to tidal volume in COPD patients seems to be greater than that of normal subjects for a given dead space. These two mechanisms are suggested to contribute to the larger increase of FETC0 2 in COPD patients.
Comparison With Previous Studies Previous studies3.4.6 have shown that Vo 2resp in patients with COPD is much greater than that in young normal subjects. Cherniacl2 reported that the mean oxygen cost was 1.16 milL ventilation in 16 normal subjects (21 to 43 years), while it was 5.96 CHEST I 105 I 3 I MARCH, 1994
795
mVL ventilation in 22 older emphysematous subjects (47 to 73 years). McGregor and Becklake4 reported that the Vo2 resp was 4.9 to 65.7 mVmin in three older patients with emphysema (49 to 66 years) but was 1.3 to 5.5 mVmin in five normal subjects (28 to 44 years). Furthermore, Campbell et al6 reported results in a 59-year-old patient with emphysema that were similar to those of a 31-yearold normal subject. However, these previous studies did not compare the Vo 2 resp between COPD patients and normal subjects in the same age range. Because we found in our previous study that 4logVo 2 tot/.1VE increased significantly with age/ Vo2resp in patients with COPD should be compared with that of normal subjects in the same age range. Based upon these studies, we measured the Vo 2 resp in COPD patients and normal subjects in the same age range, and our results confirmed that there is a significant difference of approximately 2.8 times higher mean Vo 2 resp at any VE in COPD patients than in age-matched normal subjects (Fig 4). If we could eliminate the aging effect on Vo2 resp of COPD patients, we may conclude that the observed increment of Vo 2resp in the COPD patients is caused by pathophysiologic factors.
Possible Mechanisms in Increment of Respiratory Muscle Oxygen Consumption In the COPD patients, the values of .1logVo2totl .1VE had wider variability than those of elderly and young normal subjects, as shown in Figure 4. There might be several mechanisms that contribute to the increment of .1logVo2tot/.1VE in the COPD patients. The first possibility may be that the differences between lung function at rest breathing resulted in the differences during the dead space loading. The Vo 2 resp might be closely related to mechanical impedance of the respiratory system, which is determined by resistance, compliance, and inertia of the lung and chest wall. We speculate that an increase in airway resistance and a decrease in lung compliance would increase the resistive and elastic work of the respiratory muscles, respectively. In the present study, the Cst in the COPD patients was not significantly different from that in normal subjects. Therefore, the remarkably increased R1 in COPD seems to contribute to increase the overall impedance of the respiratory system and may contribute to an increase in the Vo2 resp. Recent studies have shown that hyperinflation of the lung increases the Vo 2 resp in normal subjects. Collett and Engel 20 reported that when normal subjects increased FRC to 37 percent of inspiratory capacity, the oxygen cost of breathing was significantly increased by 41 percent, from 109 mVmin at FRC. McCool et al 21 also reported the same effect 796
on the oxygen cost of breathing. They speculated that this increment in oxygen cost may be due to changes in mechanical coupling in the pattern of recruitment of the respiratory muscles or changes in the intrinsic properties of the inspiratory muscles at shorter length (ie, at higher lung volume). Although we recognized a significantly greater percentage of FRC in patients with COPD than in normal subjects, the increment in Vo2 resp during dead space loading could not be explained by the change in FRC because we maintained the initial FRC constant during the measurement. The malnutrition in patients with COPD may be associated with the increment in Vo2 resp. Arora and Rochester2 reported that poorly nourished patients had reduced P1max and PEmax and maximal voluntary ventilation. Furthermore, Donahoe et al 23 reported that 0 2 cost was significantly elevated in malnourished patients with COPD (4.28 ml 0/L ventilation) relative to a normally nourished group (2.61 ml 0/L ventilation), and the measured resting energy expenditure also was increased compared with predicted values for the normally nourished population. These reports suggest that malnutrition seems to adversely influence respiratory muscle strength, and the combination of increased 0 2 cost and reduced muscle strength could be presented in the COPD patients. In the present study, the mean weight of the COPD group was significantly lower compared with that of normal subjects (p < 0.01), and both P1max and PEmax of COPD patients were significantly reduced (Table 2). It is difficult to determine the cause; however, we may suggest that the increase ofVo2 resp might be influenced by body weight and muscle strength in the COPD patients. The present study showed that Vo 2tot increases are associated with an increase in P0.1 in COPD patients and normal subjects and that Vo 2tot at a given P0.1 was the same between both groups. These suggest that respiratory Vo 2 has a good correlation with the output of the respiratory controller. Perhaps an increase in neural activity of the respiratory controller would cause an increase of respiratory muscle contraction, resulting in an increase in respiratory Vo 2 • In conclusion, COPD patients showed significantly higher Vo2 resp than that caused by the aging effect of normal subjects. This increase might be related to the total effect of deterioration of lung function and respiratory drive. ACKNOWLEDGMENT: We gratefully acknowledge the assistance of Mr. B. Bell in the preparation of this manuscript.
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