COPD and Human Diaphragm Muscle Dimensions*

Transcription

1 COPD and Human Diaphragm Muscle Dimensions* Narinder S. Arora, M.D., FC.C.P. ; and Dudley F Rochester, M.D., FC.C.P. To assess the effect of COPD on diaphragm muscle dimensions, we measured diaphragm muscle mass, thickness, area, and lengths in 18 COPD patients at necropsy. We compared these results with data obtained from 22 non COPD patients matched with regard to age, height, weight, and sex distribution. In the COPD patients, diaphragm muscle mass was 213±SD 69 g, thickness was.320±.055 em, area was 647±160 em", coronal muscle length was 27.8±4.0 cm and sagittal muscle length was 15.8±2.8 em, These values were within ± 8 percent of the comparable values in the non-copd patients, with no significant differences. There was no correlation between diaphragm length and lungvolume in 13COPD patients with TLC and ten with RV measurements. We conclude that over the range oflung volume encountered (TLC 135± 28 percent predicted, RV 102± 29 percent predicted TLC), there is no evidence for permanent shortening of the diaphragm. Chroni c obstructive pulmonar y disease (Ca P O) could alte r th e mass, thickn ess, area, and len gth of diaphragm muscle in several ways. For example, th e diaphragm might become hypertrophied in response to the increased work of breathing. Alternatively, in underweight capo pati ents, the diaphragm might be atrophic as has be en found in underweight patients without COPD. l Hyperinflation of the lung displaces th e diaphragm caudad. This should reduce the area of th e mu scular part and shorten muscle length. 2-4 Acute shorte ning should not alter muscle mass, but would be expected to increase muscle thi ckn ess. Howev er, in chronically shortened hamster diaphragms, muscle fiber length is reduced, mediated by loss of sarcomeres. P" If this occurs in human capo, diaphragm muscle mass and area would b e reduced, even if muscle thickness were unchanged. Previous studies of the human diaphragm in capo have yielded variable results. Ishikawa and Hayes" found diaphragm muscle mass and thickness to be greater in normal weight capo patients than in chronicallyill underweightpatients withoutcapo. In contrast, Steele and H eard" showed that diaphragm muscle volume and thickness were reduced in underweight patients with chronic bronchitis, as compared to a group of normal weight pati ents without capo. Thurlbeck" found that diaphragm weight and body weight were reduced in patients with emphysem a. Th e area of the diaphragm in COPO has been reported to be normal" or reduced.v' whereas the area of th e central tendon is unaffected by COPD. 2 *From the Pulmonary Division, Depart men t of Inter nal Medicine. University of Virginia School of Med icine, Chnrloucsvl lle. This study was suppo rted by atlonal Heart, Lung, and Blood Institute gra nts HL ami HL Manuscript rece ived March 14; revision accep ted November 11. Reprint requ ests: Dr. Rochester, Box 225, Unive rsity of Virginia Met/ictl[ Centcr, Charlottesoille The inconsistency of the results of previous studies is in part due to differences in techniques used to measure diaphragm muscle dimensions, and in part to variations among the control populations. Therefore, we measured diaphragm muscle dimensions at necropsy in 18 patients with capo and compared the results with data previou sly obtained by th e same technique in 22 patients without chronic lung disease and 16 normal subj ects. 1 Patients METHODS The study population was comprised of patients with a clinical diagnosis of capo who died at the University of Virginia Hospital. There were 13men and five women, aged 46 to 76 years. The diagnosis of COI' 0 was establi shed from their clinical history, available arterial blood gas and pulmon ary function data, and post mortem findings. Symptoms includ ed chronic cough, sputum production, and dyspnea. The patients had smoked cigarettes for 45 to 100pack years. Physical findings includ ed wheezes, rhonchi, and diminish ed breath sounds. Chest x-ray films were consistent with hyperinflation of the lungs. Final admission diagnoses included acute respiratory failure due to acute bronchitis, pneum onia, or pulmonary embolism (nine), acute myocardial infarction (four), stroke (three), esophageal carcinoma (one), and upp er gastrointestinal bleeding (one). No patient was being mechanically ventilated at the time of death. Patients with restrictive lung diseases, neuromuscular disease, obes ity, and overt ede ma were excluded from the study. Pulmonary function tests included forced vital capacity (FVC), forced expiratory volume in one second (FEVJ, and lung volumes. Fifteen patients had FVC and FEV, measured, five of whom did not have lung volumes. Total lung capacity (TLC) was measured roentgenographically" in 13 patients who had recent posterior-anterior and lateral chest x-ray films taken while standing, at a distan ce of two meters. This method has been shown to yield values for TLC in capo patients which are very close to those measured pleth ysmographically.p" Three of these patients did not have spirometry. Residual volume (RV)was calculated in ten patients as the difference between TLC measured roentgenographically and vital capacity measured spirometrically. Patients included in the study eith er had an obstructive pattern on spirometry, an increase in TLC, or both. At necropsy, body weight and height were recorded, and the CHEST I I MAY,

2 predicted ideal body weight was calculated from sex and height according to the Metropolitan Life Insurance tables" after taking into account the allowance for shoes. Thirteen patients were classified as normal weight since their bodyweight lay between 86 and 124 percent of ideal, and five as underweight since their body weight was 74 to 83 percent of ideal. The post-mortem examination of the lungs did not include quantitative morphometric analysis. However, in each case, the pathology was characteristic of chronic bronchitis and emphysema, in varying proportions. We selected from our previously reported study of diaphragm muscle dimensions! two control populations to compare with the COPD patients. The selection criteria were to match the COPD patients with respect to ranges of age and body weight. From the '27 previously reported normal subjects, 16 men met these criteria. They had died suddenly of acute myocardial infarction (10), trauma (four), and stroke (two), but they were clinically normal prior to death. From the 37 previously reported normal weight and underweight patients, 22 met the selection criteria. These patients had died in hospital after several weeks to months of a variety of diseases including neoplasm (nine), stroke (six), renal failure (three), hepatic failure (two), and myocardial infarction (two). Among these 22 patients, 16 had body weight of88 to 114percent ideal, and six were significantly underweight with body weight 75 to 81 percent ideal. Patients with obesity, myopathy, obvious edema, or any type of chronic lung disease were excluded. Diaphragm Muscle Dimensions cleaned of fat and other nondiaphragmatic tissue, and measured as previously described.' The mass of diaphragm muscle (DMM) and central tendon were determined by weighing, and the volume of the graduated cylinder. To measure areas, the whole diaphragm was spread flat on a large sheet of paper, and the outlines of the whole diaphragm and the central tendon were traced. These outlines were subsequently traced onto a clean sheet of paper, and the areas were measured using a planimeter. The area of the muscular portion was determined as the difference between the area of the whole diaphragm and central tendon. The mean thickness of the muscular portion (DMT) was calculated as the ratio of muscle volume to muscle area. The linear dimensions of the diaphragm were measured along two diameters corresponding to coronal and sagittal sections throughthe body. Along each diameterthe total length, the lengthof the muscle (DML), and the tendon length were recorded. Statistical Analysis The data in text and tables are reportedas mean ± standard deviation (SD). Statistical analyses included Student's t-testfor differences between group means, and least squares linear regression analysis." Analysis ofcovariance was usedto compare the slopes and intercepts of two linear regressions." RESULTS Vital statistics of the COPD patients, the matched non-copd patients and normal subjects are summarized in Table 1. The two patient groups were virtually identical with regard to sex distribution, age, height, weight, and body weight expressed as percentage of ideal weight. The matched normal subjects were all men. They were not significantly different from the COPD patients with regard to weight, but were slightly heavier than the matched non-copd patients. The pulmonary function data of the COPD patients Table I-Vital Statistics ofcopd Patients, Patients Without COPD, and Normal Subjects Non-COPD Matched COPD Patients* Normal Subjects* Sex 13M,5F 16M,6F 16M Age (yrs) 65±8 64±11 62±13 Height (em) 168±8 170±9 172±9 Weight (kg) 62.8± ± ±8.0t Weight (% ideal) 98±16 92±13 102±9t *Selected from patients and normal subjects previously reported' so as to match COPD patients with regard to age and weight. tsignificantly higher than matched non-copd patients (p<0.05). are summarized in Table 2. All 15 patients with spirometric measurements exhibited an obstructive pattern (FEV l range 11 to 56 percent predicted). Of the 13 patients with lung volum e measurem ents, TLC was elevated in 12 (range 109 to 180 percent predicted). The exception, whose TLC was 87 percent predicted, had an obstructive pattern on spirometry. In the 12.patients in whom recent room air blood gas composition was available, PaC0 2 averaged 47 ± 10 mm Hg and Pa0 2 was 48 ± 13 mm Hg. Diaphragm muscle dimensions are summarized in r'd_ L 1 _ f"l rpl p _ 1 N' 1.1<tUl<:; o.111<:;1<:; W<:;I<:; uu ~ 1 g, 1 1 1U1U1 l c< a: U; ll uelweeu < : ; u c e ~ the mass, thickness, area, or length dimensions of COPD patients and non-copd patients matched for a ze and wei ht, The same holds when normal wei ht and underweight patients of each group were compared with each other. In the underweight COPD patients, diaphragm muscle mass and area were significantly (p<0.05) lower than in the normal weight COPD patients, but the other dimensions were not Table 2-Pulmonary Function Data ofcopd Patients* Forced vital capacity (% pred) Forced expiratory volume in 1 sec (% pred) Maximal voluntary ventilation (% pred) Total lung capacity (% pred) Residual volume (% pred TLC) 48±15 31±14 25±17 135±28 102±29 *Numbers in parentheses are the number of patients in whom the measurement was available. Table 3-Diaphragm Muscle Dimensions in COPD Patients and Matched Normal Subjects (15) (15) (8) (13) (10) Matched COPD Non-COPD Normal Patients Patients Subjects Muscle mass (g) 213±69 210± ± 44* Muscle mass/body wt 3.34± ± ±.41* (g/kg) Muscle thickness (em).320± ± ±.037 Muscle area (em') 647± ± ± 114* Coronal muscle length 27.8± ± ±3.8* (em) Sagittal muscle length 15.8± ± ±2.7* (em) *Significantly higher than COPD value (p<0.05). 720 COPDand HumanDiaphragm Muscle (Arora, Rochester)

3 DMM (g) o Body Weight (kg) F IGURE 1. Relationship between diaphragm muscle mass (DMM) and body weight in normal weight (circles) and und erweight (triangles) COPD patients. Open symbols denote female, and closed symb ols male patients. The solid regression line is calculated from the COPD patient data; its equation is DMM = 4.95 BW (r=.89, p<o.ooi). The dashed line and shaded area represent the regression ± SEE for matched patients without chronic lung disease. The slopes and intercepts of the two regressions are not significantly different. significantly different. Mean values for diaphragm muscle mass, area, and length were lower in the COPD patients than in the matched normal subjects (p < O.05). However, when the ten normal weight male COPD patients were compared with the normal subjects, these differences were no longer stati stically significant. The ratio of diaphragm muscl e mass to body weight averaged 3.66 ±.64 glkg in norm al weight male COPD patients, which was significantly lower (p<o.05) than in the matched normal subjects. Th e area of the central tendon was the same in all three groups. The relationships between diaphragm muscle mass.5.4 DMT(cm) Body Weiaht lkn\ FIG URE 2. Relati onship betw een diaphragm muscle thicknes s (DMT) and body weight in normal weight (circles) and underweight (triangles) COPD patients. Open symbols denote female and closed symbols male patient s. The solid regression line is calculated from the COPD patient data; its equation is DMT = BW +.lis (r =.71, p<o.ooi). The dashed line and shaded area represent the regression ± SEE for matched patients without chronic lung disea se. The slopes and intercepts of the two regressions are not Significantly different ' and bod y weight, and between diaphragm muscle thickness and body weight are shown in Figures 1 and 2. For purposes of comparison, th e regression lines ± 2 standard errors of estimate (SEE) for non-copd patients are also shown. It can be seen that virtually all data points from COPD patients lie within ± 2 SEE of the regressions for patients without COPD. Mor eover, the slopes and intercepts of th e regression lines for COPD patients are not significantly different from those calculated for patients with COPD. We also compared these relationships in the COPD patients with the corresponding relationships in the matched normal subjects. The slope of the regression of diaphragm muscle mass on bod y weight in COPD patients was not significantly different from that for normal subjects. However, the intercept was significantly lower (p<o.005). Thus, for a patient weighing 62.8 kg, the average weight of the COPD patients, diaphragm muscle mass calculated from the COPD regression would be 213 g, wher eas the value calculated from the regression for age and weight matched normals is 249 g. The slope and intercept of the regression relating diaphragm mu scle thickness to body weight in COPD subjects were not Significantly different from those in normal subjects (data not shown). Diaphragm muscle length varies with the size of the individual. Therefore, to better assess whether diaphragm muscle len gths were shorter in the COPD patients than in non-copd patients or normal subjects, we calculated a diaphragm muscle length index (D MLI).IB The DMLI is the sum of the coronal and sagittal muscl e lengths, divided by height. In normal DMLI (em/em). 1 0 o NL NW ALL NON COPO COPO CO PO FIGURE 3. Comparison of diaphragm muscle length index (DMLI) among four groups ofpatients. Barslabelled "NW-COPD" and "ALL capo" represent the 13 normal weight and all IS COPD patients, respectively. Bars labelled "NL" and "NON-Ca PO" refer to age and weight matched normal subjects and patients without chronic lung disease, respectively. The height of the hatched bar repr esents the group mean, and the small bars are 1 SD higher. The asterisk indicates significantly lower than group NL and the dagger significantly lower than group NW-COPD (p<0.05). CHEST / 91 / 5 / MAY

4 subjects and normal weight non-copd patients, diaphragm muscle length was significantly correlated with height (p<0.02), and the intercept of the regression was not significantly different from zero. Moreover, expressing diaphragm muscle length as DMLI eliminates sex-related differences in diaphragm length." Thus, 0 MLI was relatively constant in normal subjects and normal weight non-copd patients. The mean values of DMLI in COPD patients, non COPD patients and normal subjects are shown in Figure 3. The DMLI values in COPD patients were slightly but not significantly larger than those in non COPD patients. In the age-matched normal men, mean DMLI was larger than in either patient group. However, in the 13 normal-weight COPD patients, DMLI was not significantly different from that in normal subjects. The relationships between DMLI and eithertlc or RVare shown in Figure 4. Over a range oftlc of 87 to 180 percent predicted, and a range of RV of 59 to 147 percent predicted TLC, there was no correlation between DMLI and either of the lung volumes DMLI (em/em) L- l-.l-.l..-_---' RV (% PREDICTED TLC).10 L- 1-_-.ll.-_----L ----' DMLI (em/em) TLC (% PREDICTED) FIGURE 4. Plot of diaphragm muscle length index (DMLI) and residual volume (RV, upper panei; or total lung capacity (TLC, lower panen. Circles represent normal weight COPD patients and triangles are underweight COPD patients. There is no relationship between DMLI and lung volume in these patients. DISCUSSION Comparisons Among Patient Groups This study shows that the dimensions of diaphragm muscle, that is, its mass, thickness, area, and lengths along coronal and sagittal diameters, are essentially the same in 18 patients with COPD as in 22 patients without COPD. Since the two groups are virtually identical with regard to sex distribution, age, height, and body weight, the dimensions can be compared directly. Because the COPD group comprises some women and some underweight patients, it is not surprising that the mean values for diaphragm muscle mass, area, and length are lower than in 16 age matched normal weight men. However, when the ten normal weight male COPD patients are compared with the normal men, these differences are no longer significant. Our data on diaphragm muscle mass in COPD are quite consistent with that reported by others. Thurlbeck" found that diaphragm weight averaged 246 g in patients with emphysema grades 4 to 9 (data calculated from Fig 2 9 ). Since the muscle mass is about 90 percent of the total diaphragm weight, 1 diaphragm muscle mass in Thurlbcclcs patients is probably about 220 g, which agrees closely with our result. Ishikawa and Hayes" found diaphragm muscle mass to be g in normal weight male COPD pa en s. T lis is lig ier than our meanfigurc, ou t it agrees well with the value of 260 ± 41 g in our normal weight male COPD patients. In contrast to the agreement for muscle mass, our data differ with regard to muscle thickness and area. Ishikawa and Hayes" calculated mean muscle thickness as the quotient of muscle mass and area. They found a value of.50l±.082 em in normal weight male COPD patients. Conversely, Steele and Heard 4 found by direct measurement that diaphragm muscle thickness was. 234 ±.032 em in underweight male patients with chronic bronchitis. This is somewhat lower than the value of.283±.034 em in our five underweight COPD patients, and might reflect the site which Steele and Heard" selected to measure thickness. Steele and Heard" found that the area of diaphragm muscle was lower in male subjects with chronic bronchitis than in control subjects, but their technique for measuring area yields such numerically different values that they cannot be compared with ours. Butler" and Ishikawa and Hayes" measured diaphragm muscle area much as we did and found values in their male COPD patients about 30 percent lower than ours. This would correspond to about a 15 percent reduction in muscle length. The reason for the difference in the results is not apparent, since the other investigators did not provide lung volume data. One can hypothesize that if their patients' lungs were more hyperinflated than in our patients, the diaphragm would be 722 COPDand HumanDiaphragm MusCle (Arora, Rochester)

5 displaced caudad. Acute hyperinflation could cause increased diaphragm muscle thickness and decreased muscle area, which is consistent with the results of Ishikawa and Hayes." Alternatively, reduction of muscle area in chronically hyperinflated patients could reflect permanent shortening of diaphragm muscle, as occurs in emphysematous hamsters.r" Without lung volume data and direct measurement of the length and number of sarcomeres in human diaphragm muscle, we can only speculate as to the reasons for the differences in diaphragm muscle thickness and area in different studies. Lung Volume, Diaphragm Muscle Length and Sarcomere Adaptation It has been hypothesized that the number of sarcomeres in a striated skeletal muscle fiber is adjusted so as to provide for optimal sarcomere length when the muscle is at the length at which it most commonly develops high levels of active tension." Sarcomere adaptation refers to an adjustment in the number of sarcomeres consequent to an intervention which permanently lengthens or shortens a muscle from its usual in situ length. For example, immobilizing legs of adult cats in dorsiflexion or plantar flexion either lengthens or shortens the soleus muscle. After four weeks of immobilization, the number of sarcomeres in lengthened muscle fibers increased by 20 percent, whereas the number in shortened muscles decreased by 40 percent. 20 The loss of sarcomeres in shortened muscles is not influenced by placing the muscles at rest or in a state of chronic contraction. 21 In these studies, the threshold degree of shortening required to induce loss of sarcomeres was not defined. In the hamster model of emphysema, the resting length of the diaphragm is shortened on average by about 15 percent. 5-8 This is accompanied by a 10 percent loss of sarcomeres.t" As a result, the remaining sarcomeres are nearer to their optimal resting length, and the chronically shortened diaphragm can generate the same force as control diaphragms. If there had been no sarcomere adaptation, shortening of the diaphragm by 15 percent would have reduced its maximal force output by approximately 15 percent. Since we did not find any evidence for shortening of the diaphragm in COPD patients studied at necropsy, we must address the question of how much hyperinflation of the lung is required to shorten the diaphragm enough so that permanent shortening could be identified at necropsy. We do not think that our results are influenced by technical problems such as postexcisional contraction of the diaphragm. In the control and COPD groups, the diaphragms were excised between two and 12 hours after death, and the measuring techniques were identified for all groups. At necropsy, the transverse diameter of the in situ diaphragm, measured along its convex curvature, is not significantly different from the transverse diameter of the excised diaphragm flat on the table. 1 Rigor mortis is highly unlikely to have influenced the results, because muscles in rigor generally do not shorten. 22 A much more plausible hypothesis is that the lungs of our COPD patients were not as severely hyperinflated as those of the emphysematous hamsters. In those patients whose lung volumes could be estimated, TLC averaged 135 percent predicted, and RV was 102 percent predicted TLC. Since RVin normal subjects of this age is typically about 35 percent of predicted TLC, 23 that means the RV of our subjects was approximately three times normal. Thus, the FRC of our COPD patients was probably 1.5 to two times normal. This degree of hyperinflation is consistent with the results of other reports In the hamster model of emphysema, the degree of pulmonary hyperinflation is much greater than in typical human COPD. On average, the TLC was 1.7 times normal and FRC was two to three times normal. Supinski and Kelsen" plotted the relationship between optimal resting length of the diaphragm and the number of sarcomeres in diaphragm muscle fibers. Costal diaphragm strips were obtained from normal hamsters and emphysematous animals whose TLC averaged 1.6 times normal. Data points from diaphragm strips of normal and emphysematous animals closely fit a single straight line, indicating a tight relationship between muscle length and sarcomere number. There was, however, a marked degree of overlap between data points of normal and emphysematous animals, such that in 11 of 16 diaphragm strips from emphysematous hamsters, length and sarcomere number lay in the lower halfof the normal distribution. Farkas and Roussos" also found substantial overlap of diaphragm lengths from normal and emphysematous hamsters. We have tabulated results of their Figure 9 so as to divide the emphysema group into mild, moderate, and severe categories (Table 4). Overall, eight ofl8 diaphragm lengths from emphysematous animals lay in the normal range; the distribution by group is shown in the table. From these data, we can predict that when emphysema causes FRC to increase 1.5 to twofold, the Table 4-Diaphragm Length as a Function ofthe Severity ofemphysema in Hamsters* FHC DML No. with DML Group ml/kg % cm % in Normal Range Normal lli11 Emphysema I /5 Emphysema /6 Emphysema /7 *Definition of abbreviations: FRC is functional residual capacity; DML, optimal length of diaphragm muscle. Mean values calculated from Figure 9.' CHEST I I MAY,

6 optimal resting length of the diaphragm will be 97 to 94 percent of normal. In living patients with capo, the impact on diaphragm length is also relatively small. We measured the length of the diaphragm at RV using a roentgenographic technique and related diaphragm length to lung volume. 27 The average length at RV in capo patients was 28 percent shorter than the average length at RV in normal subjects.18 However, the average diaphragm length at RVin capo patients was only 4 percent shorter than the length of the normal diaphragm at FRC. Since RV and FRC are close together in capo, we think that the length of the diaphragm at FRC in patients with capo is only slightly shorter than the length at normal FRC. Twoother factors also bear on the effect of capo on diaphragm length. The linear diameters across the chest increase by about 15 percent as lung volume increases from RV to TLC. 18 Thus, at higher lung volumes, even though the dome of the diaphragm is lower, the diaphragm has to span a broader width. Moreover, Sharp et al" have recently shown roentgenographically that patients with quite severe emphysema may increase their lung volume primarily by expansion of the upper rib cage. In such patients, one would also expect copo to have only a small effect on diaphragm length. In snmmrrry;,ve found tllut OliOI tho l U U Cof~ luug volumes encounteredin ourcapo patients, therewas no obvious shortening of diaphragm muscle. In all respects, the gross dimensions of diaphragm muscle were virtually identical to those of patients without chronic lung disease, matched for age, sex, and weight. We conclude that human capo probably has a relatively small effect on diaphragm length, based on data from animals and living capo patients. However, we by no means exclude the possibility that patients with more severe emphysema, such as many of Sharp's patients,":" could be found to have shortened diaphragms. We estimate that FRC would have to be two to three times normal, and TLC 1.5 times normal to demonstrate the phenomenon. ACKNOWLEDGMENT: We thank Mrs. Betty Edmondson for her help in preparing the manuscript. REFERENCES 1 Arora NS, Rochester OF. Effect of body weight and muscularity on human diaphragm muscle mass, thickness, and area. J Appl Physiol Respir Environ Exer Physiol1982; 52: Butler C. Diaphragmatic changes in emphysema. Am Rev Respir Dis 1976; 114: Ishikawa S, Hayes JA. Functional morphometry ofthe diaphragm in patients with chronic obstructive lung disease. Am Rev Respir Dis 1973; 198: Steele RH, Heard BE. Size of the diaphragm in chronic bronchitis. Thorax 1973; 28: Farkas GA, Roussos C. Adaptability of the hamster diaphragm to exercise and/or emphysema. 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