EFFECTS OF INACTIVITY, WEIGHT GAIN AND ANTITUBERCULAR CHEMOTHERAPY UPON LUNG FUNCTION IN WORKING COAL-MINERS

Ann. Occup. Hyg: Vol. 10, pp. 327-335. Pergamon Press Ltd., 1967. Printed in Great Britain EFFECTS OF INACTIVITY, WEIGHT GAIN AND ANTITUBERCULAR CHEMOTHERAPY UPON LUNG FUNCTION IN WORKING COAL-MINERS J. E. COTES and J. C. GILSON Assisted by CYNTHIA JOHN Pneumoconiosis Research Unit of the Medical Research Council, Llandough Hospital, Penarth, Glamorgan (Received 9 February 1967; in revised/arm 30 March 1967) Abstract-Lung Function and Physiological responses to sub-maximal exercise have been studied in 113 working coalworkers with early progressive massive fibrosis (Category A) before and after a 3 month period in a sanatorium, and again 9 months later. Over the period, half these subjects received antitubercular chemotherapy. They were selected at random from a larger group of whom the remaining 57 men continued to work in the mines: they were also studied as controls. The period in a sanatorium without chemotherapy was associated with a gain in body weight which resulted, at rest, in significant reductions in forced expiratory volume, forced vital capacity, functional residual capacity and radiological lung area; during exercise there were proportional increases in oxygen consumption, cardiac frequency and ventilation minute volume. Apart from effects due to the gain in weight, withdrawal from the mines and associated inactivity had singularly little effect upon physiological function. Antitubercular chemotherapy had the effect of lessening the gain in weight which would otherwise have occurred in the sanatorium. It had little direct effect upon performance. Inactivity impairs the function of the circulation and the strength of skeletal muscles (e.g. TAYLOR et al., 1949). On theoretical grounds, it may also affect indices of lung function, including vital capacity, (HUTCHINSON, 1846), and transfer factor (diffusing capacity, COTES, 1967); however, no practical study of inactivity and lung function appears to have been undertaken. We have, therefore, used the opportunity of a controlled therapeutic trial for early progressive massive fibrosis of coalworkers, (GILSON, 1964), to examine this subject, which may be important for medical rehabilitation, as well as for understanding the mechanism of physical training. The results suggest that a 3 month period of relative inactivity following withdrawal from mining has little direct effect upon lung function or performance of submaximal exercise; it may however lead to an increase in body weight which has a deleterious effect. METHODS THE SUBJECTS were 170 working coalworkers under the age of 50 years, with no significant disease other than early progressive massive fibrosis (Category A) for which they agreed to take part in a trial of treatment. For this purpose, they were allocated at random to one of three groups; Group A received rest and antitubercular chemotherapy; Group B received rest but no significant chemotherapy, whilst Group C continued at work without treatment. The rest took the form of 3 months in a Sanatorium; for the first 2 weeks the subjects were mainly in bed, then for the next 6 weeks they were partly in bed, with increasing periods of being up, and for the 327

328 J. E. COTES and J. C. GILSON last 4 weeks they were up all day. Most of the time out of bed was spent seated, but the subjects were able to do handicrafts, including carpentry, play table tennis and take walks out of doors. Chemotherapy for subjects in Group A comprised a daily dose of streptomycin 19, isoniazid (INH) 200 mg and p-aminosalicyclic acid (PAS) 109 for 3 months, followed by INH and PAS for the succeeding 9 months. The subjects attended for investigation before the start of the trial, then about 3! months and 12 months later. At the time of the second attendance, those previously in the Sanatorium (Groups A and B) had been discharged, but usually had not returned to work. At each attendance all subjects received a clinical examination, chest radiograph and assessment of ventilatory capacity: the lung volumes and transfer factor (diffusing capacity of the lungs) were measured in 11 subjects each from groups Band C, and the physiological response to exercise was assessed in 53 subjects, divided nearly equally between the 3 groups (17 or 18 per group). The tests of ventilatory capacity used were, the forced expiratory volume (FEV o 75 ) and forced vital capacity (FVC); they were measured using the technique of McKERROW et al. (1960). The lung volumes were measured by the closed-circuit helium-dilution method and the transfer factor by the single-breath method; these procedures and also those for exercise (see below) are described in detail elsewhere (COTES, 1965). The response to exercise breathing air was assessed in terms of ventilation minute volume, cardiac frequency and respiratory frequency, both at rest and during the 4th-6th minutes of walking on a motor driven treadmill at 2 m.p.h. on the flat and at 2 5 m.p.h. up an incline of 1 in 10. The subjects were then switched to breathe oxygen and the measurements during exercise repeated. The data were analysed separately for the 3 levels of activity; those for exercise were also standardised to an oxygen consumption of 1 5 l.jmin as recommended in the recent I.L.O. Committee Report, Pulmonary Function Tests in Pneumoconioses (1966). For this purpose, linear regressions of ventilation minute volume, cardiac frequency and respiratory frequency on oxygen consumption were assumed. Body weight RESULTS The initial mean body weights ofthe subjects in the 3 groups were nearly identical' (Table 1). In the subjects who entered the Sanatorium (Groups A and B) the weights increased significantly over this time. The average increase was somewhat greater (p < 0'05) in subjects of Group B, who received no significant drug treatment, than in those of Group A who were on full antitubercular chemotherapy (4,1 and 2 5 kg respectively). The weights, on average, nearly reverted to their initial values during the 9 months after the subjects left the Sanatorium. In the subjects who remained at work throughout the period of observation (Group C) the mean weight did not change to a material extent. Ventilatory capacity The initial values for the subjects in the 3 groups were nearly identical (Table 1). In the subjects of Group B who entered hospital, but received no other treatment,

Inactivity, weight gain and lung function 329 TABLE 1. BODY WEIGHT, FORCED EXPIRATORY VOLUME (FEVo. 7 6 ), FORCED VITAL CAPACITY (FVC) and RADIOLOGICAL LUNG AREA (LA) MEAN VALUES OVER 12 MONTHS FOR ALL SUBJECTS Number Age Weight Height FEVo. 7S FVC LA years kg m 1. l. cm ll Group A (rest and chemotherapy) Initial 57 44 3 68-9 1'67 2-69 4 01 480 3 months *71-4 *2'63 3-97 476 12 months 69-1 *2-56 3-99 486 Group B (rest) Initial 56 43'8 69-5 1-68 2'69 3 98 419 3 months *73-6 *2,60 *3-89 *466 12 months 70-8 *2,60 3 94 475 Group C (normal activity) Initial 57 43 6 69 1 1 69 2-71 4 00 491 3 months 69 0 2'70 4-04 492 12 months 69'7 *2,65 4 07 492 *Change from initial value within a group (p < 0 '05). the forced expiratory volume and forced vital capacity decreased significantly over. the first 3 months of the trial, both in absolute terms and relative to the subjects of Group C who remained at work (Fig. 1). In the subjects of Group A, who received FYC,I FEY o 75,1 wt, kg. 2.7t 2.6 73T 6J ~... '"'" " "",. -------0, --... ~- ~)(... -- -- --- -- 0------0--- )(, ------ --..,.... - -- --)(, ------- " ~, 'x- - - - - - - - - - - - - - - - - ->c x.. _ "" fi'......--- " --- " --- " --- ~... -~ 0 0 InactiVity 3 6 9 12 (Group B) Months FIG. 1. Effect of inactivity over 3 months upon body weight, forced expiratory volume (FEV 007 6 ) and forced vital capacity (FVC) in coal workers with category A progressive massive fibrosis. Inactivity (Group B) x - - - x, Control (Group C) 0--0.

330 J. E. COTES and J. C. GILSON chemotherapy in hospital, the forced expiratory volume was 'also reduced, but to a smaller extent. After leaving hospital the trend of results was generally reversed but, for all groups, the mean values at the end of 12 months were significantly less than those observed initially. The average decline over 12 months was from 2 70 to 2 60 1: there was no corresponding change in forced vital capacity (mean value 4 00 1. on both occasions). The changes in ventilatory capacity over the first 3 months for all subjects together were weakly correlated (p<0 05) with the changes in body weight (correlation coefficients for FEVo' 75 and FVC on body weight respectively - 0 157 and - 0,168). Lung areas The areas of the lung fields on the postero-anterior chest radiographs were initially similar for all three groups of subjects (mean area 483 em"): the area decreased by 12 6 em- (p<o Ol) over the next 3 months in those subjects who entered hospital but received no other treatment (Group B). This change was reversed over the following 9 months. No material change in area occurred in the other groups (Table 1). Lung volumes and transfer factor Mean values for the total lung capacity and transfer factor, also their subdivisions in the 11 subjects in Groups Band C, are summarised in Table 2; this shows that the TABLE 2. LUNG VOLUMES AND TRANSFER FACTOR: MEAN VALUES OVER 12 MONTHS IN GROUPS OF 11 SUBJECTS Weight TLC FRC RV RV%TLC Tl kg 1. 1. 1. Group B (rest) Initial 76 9 6 12 3 25 2 12 34 0 27 5 3 months *80,5 6 06 *3,10 2 21 36 0 28 0 12 months 76 6 6 09 3 29 2 25 36 3 28 5 Group C (normal activity) Initial 74 0 6 72 3'67 2 52 37 4 28 1 3 months 73 3 6 77 3 85 2'53 37 0 26 7 12 months 74 6 7 20 4 15 2 83 38 1 28 2 *Change from initial value for Group B relative to Group C (p < 0 '05). TLC total lung capacity FRC functional residual capacity RV residual volume RV%TLC residual volume as percentage of total lung capacity Tl transfer factor (diffusing capacity of the lung) initial function was, on average, similar for those who entered hospital and those who remained at work (Groups Band C respectively). Whilst in hospital, subjects in Group B experienced a significant gain in weight; they also incurred a reduction in functional residual capacity (p<0 05). Both indices reverted to their initial values over the subsequent 9 months.

Physiological response to exercises Inactivity, weight gain and lung function 331 The findings for rest and the higher level of exercise breathing air, on 17-18 subjects in Groups A, Band C, are summarised in Table 3. This shows that the mean function at the start of the trial was similar for those subjects in the 3 groups on whom the measurements were made. The subsequent changes in body weight for these subjects resembled those for the groups as a whole. Subjects in Group C, who remained at work, showed a progressive reduction in cardiac frequency during exercise over the period of the trial. This was accompanied by a small reduction in oxygen consumption: on this account the change was no longer significant when the data were standardised to an oxygen consumption of 1 5 l/min. The respiratory frequency and, to a lesser extent, the ventilation during exercise, also showed reductions over 3 months, but the latter change might well have occurred by chance (p < 0,20). No material changes for the other indices were observed in this Group. For subjects in Group A, during their time in hospital, the cardiac frequencies showed a tendency to rise. In absolute terms the rise might have occurred by chance, but it differed significantly from that which was observed in Group C. No other material change was observed in this Group. For subjects in Group B during their time in hospital, the cardiac frequencies at. rest and on exercise increased (p < 0,05) both in absolute terms and relative to the changes which occurred in the other groups. During exercise this increase in frequency was associated with increases in ventilation and oxygen consumption, (Fig. 2), V E 39 43 26 - ~ l/min per min - CF per min 35 _ RF ~ ID~ 22-0 3/12 1 yr 0 3/12 1 yr 120_ 1.8- m ~ ed 110-. V 02 I/min ~ J.6-0 3/12 1 yr 0 3/12 1 yr FIG. 2. Effect of 3 months' inactivity upon ventilation (VE) cardiac and respiratory frequencies (CF and RF) and oxygen consumption (Vo 2 ) during exercise (2'5 m.p.h., 10 per cent incline). Inactivity (Group B) hatched rectangles; Control (Group C) open rectangles. and disappeared when standardised to an oxygen consumption of 1 5 l/min. By the end of 12 months the indices resembled those in Group C in reverting to somewhat below their initial values.

TABLE 3. MEAN VALUES FOR VENTILATION (VE) RESPIRATORY FREQUENCY (RF), CARDIAC FREQUENCY (CF) AND OXYGEN CONSUMPTION (V0 2 ) Rest Exercise 2-1 m.p.h. up incline 1 in 10 V0 2 standardized to l'51/min Weight kg VE RF CF V0 2 VE RF CF V0 2 VE RF CF ~ Group A (rest & chemotherapy) t'rj Initial 70 3 11 4 18 4 74 8 0 30 37 5 23 8 120 8 1 65 34 3 23 3 114 5 (") 3 months *t73 5 12 7 18 1 t77'9 0 29 37 5 22 6 t123'6 1 64 35 0 22 4 118 2 Sl Group B (rest) 1 year 70 3 12 3 19 0 74 2 0 30 37 6 22 1 117 5 1 59 35 3 19'1 114 9 Initial 73 0 11 9 16 6 72,2 0 31 40 7 23 1 116'0 1 63 37 5 22 4 111 8 ~ 3 months *t78'0 11 8 15 7 *t77 1 0 31 t43'3 t25'2 *t122'6 *t1'79 36 6 23 4 112'7 0 1 year 73 5 12 0 17 1 72 4 0 29 38 6 24 0 112 2 1'56 37 2 23 5 109 8 0 Group C (normal activity) Initial 73 0 12 7 19 8 78 3 0 32 41 9 26 3 116 6 1 64 38 5 25'9 112 7 0 z 3 months 73 0 12 9 17 4 74 6 0 32 39 7 *24,7 113 4 1 61 37 8 24 7 111 2 1 year 73 0 12 3 18 1 72 9 0 29 39 9 25 0 *110,7 1'58 37 7 24 8 107 2 *Change from initial value within a group. tchange from initial value relative to that for Group C (p< 0'05). t"!'l tn r;l) ~ Q.. Ftn w wn

Inactivity, weight gain and lung function 333 Data for the lower level of exercise (2 m.p.h. on the flat) showed similar, but less marked, changes over the period of the trial to those observed at the higher level. At both work levels the effect of breathing oxygen was to reduce the ventilation minute volume and cardiac and respiratory frequencies: however, no significant differences between groups in their responses to oxygen was were observed. DISCUSSlON The changes in lung function for men who entered hospital (Groups A and B) can best be considered in relation to those for men who remained at work (Group C). Here, during exercise, there was a tendency for cardiac frequency, ventilation minute volume and oxygen consumption to fall over the period of the trial; these changes were probably due to increased familiarity with the test procedures (c.f. COTES and MEADE, 1959), and were not reflected in the lung function indices. Effect of gain in weight The changes in Group B during their time in hospital comprise a gain in weight, reductions in forced expiratory volume, forced vital capacity, functional residual capacity and radiological lung area and increases in cardiac frequency, ventilation minute volume and oxygen consumption during exercise. The fall in functional residual capacity is probably due to the increase in body weight; this may exert its effect through an increase in abdominal fat elevating the diaphragm, which change is shown on the chest radiographs. Between subjects of different weight a comparable variation in FRC has been observed in a cross-sectional study by GRIMBY and SODERHOLM (1963). The converse change ofan increase in FRC following weight reduction in obese subjects has been observed by BEDELL et al. (1958). The reductions in forced expiratory volume and vital capacity are of approximately equal magnitudes and negatively correlated with the changes in body weight. They are probably due to this affecting the vital capacity, and reducing the compliance of the chest wall (NAIMARK and CHERNIACK, 1960), but a possible increase in smoking whilst in hospital cannot be ruled out as a contributory cause. However, increased smoking, if it had any effect, would reduce the FEVwhilst, at the same time, minimising or reversing the gain in weight. Since the reduction in FEV disappears when allowance is made for the change in weight, there is no evidence for smoking contributing materially to the result. The observed effect on ventilatory capacity of the change in weight contrasts with the absence of a material effect in cross-sectional studies when age and height are also included in the regression relationship. In one study (COTES et al., 1966), the regression coefficients of FEV and FVC on weight in the presence of age and height were respectively -0,002 (not significant) and -0,009 (p < 0,05) l.jkg. The changes were, therefore, in the same direction, but smaller than those reported here. This may reflect the different compositions and distributions of the additional weight in the two sets of circumstances. The incomplete recovery of FVC and the absence of recovery in FE V, following return to initial weight, probably reflects in part a downward trend with time; this is larger in the present subjects with early progressive

334 J. E. COTES and J. C. GILSON massive fibrosis than in the subjects with normal lungs studied by McKERROW and ROSSITER (1967, approximately 0 11 and 0 03 1. per annum respectively). The increase in oxygen consumption during exercise in the present study is proportional and probably due to the increase in body weight. It in turn accounts for the increases in ventilation minute volume and cardiac and respiratory frequencies, because the values standardised to an oxygen consumption of 1 5 l/min remain constant over the trial. This finding is consistent with others in obese subjects before and after weight reduction (e.g. KOTILAINEN and KOTILAINEN, 1962; SALZANO et al., 1958). Thus the lung volumes, ventilatory capacity and responses to exercise are affected by changes in body weight. By contrast, the present study confirms earlier reports (e.g. BEDELL et al., 1958) that the transfer factor is independent of weight. This is to be expected since a change in weight is unlikely to affect the volume of blood in the pulmonary capillaries, whilst the induced alteration in lung volume is too small to affect the diffusion characteristics of the alveolar capillary membrane. Effect ofantitubercular chemotherapy The effect of antitubercular chemotherapy upon lung function may be assessed by comparing the findings in those who received it (Group A) with those who received treatment by rest alone (Group B). The changes over the 3 months in hospital are consistently less marked in Group A than Group B. This is probably related to their smaller gain in weight, which in turn may be the result of depression of appetite by PAS. However, the increase in cardiac frequency during exercise in excess of the increase in oxygen consumption and the failure of the frequency to fall at the end of a year, at which time some of the subjects were still on PAS and INH, may have been due to the drugs. There is no evidence to suggest an effect of the drugs on lung function, other than that mediated by the increase in weight. Effect of inactivity independent of a gain in weight Entry into hospital entailed a reduction in physical activity which might have been expected to reduce the capacity for exercise and exert a deleterious effect upon lung function. In this context, during the present study, it was intended to find out if the transfer factor (diffusing capacity of the lung) is reduced by inactivity, just as it is increased by physical training (e.g. BANNISTER et al., 1960; MOSTYN et al., 1963; COTES, 1967). In the event, no change in the, index was observed. This may be interpreted as evidence that either inactivity had no effect, or the regime was not rigorously applied; the latter would seem more likely, since although in Group B, at the end of the time in hospital, the cardiac frequency at rest was somewhat increased, the increase during exercise could be explained solely on the basis of the gain in weight. There is little evidence of loss of cardiovascular fitness, such as might have been expected to accompany a change in the transfer characteristics of the lungs. Entry into hospital also entailed a temporary withdrawal from the mines, which might have been expected to reverse any immediately deleterious effect of mining

Inactivity, weight gain and lung function 335 upon the lungs. The absence of any change in function other than via a change in body weight, is evidence against mining per se exerting an effect of this sort. It is concluded that a short period ofbed rest followed by prolonged convalescence in previously working miners has surprisingly little effect upon lung function, or performance during sub-maximal exercise, except when the regime leads to an increase in body weight. Acknowledgements-We are indebted to the National Coal Board, the National Union of Mineworkers, the Medical Superintendent and Staff of Talgarth Sanatorium, Dr. J. D. BALL and other colleagues whose participation in a trial of chemotherapy for progressive massive fibrosis made this investigation possible. We are also indebted to Mr. G. BERRY for Statistical advice and to others including the Misses A. HART, E. HUGHES, M. ROBERTS, P. TASKER and M. WALTERS and Mr. M. J. SAUNDERS for technical assistance. REFERENCES BANNISTER, R. G., COTES, J. E., JONES, R. S. and MEADE, F. (1960) J. Physiol., Lond. 152,660. BEDELL, G. N., WILSON, W. R. and SEEBOHM, P. M. (1958) J. din. Invest. 37, 1049. COTES, J. E. (1965) Lung Function; Assessment and Application in Medicine Blackwell Scientific Publications, Oxford. COTES, J. E. (1967) In Physical Activity in Health and Disease (Edited by EVANG, K. and ANDERSON, K. L.) p, 121. Universitetsforlaget, Oslo. COTES, J. E. and MEADE, F. (1959) Ergonomics 2, 195. COTES, J. E., ROSSITER, C. E., HIGGINS, I. T. T. and GILSON, J. C. (1966) Br. med. J. 1, 1016. GILSON, J. C. (1964) The Marc Daniels Lecture of the Royal College of Physicians, London. GRIMBY, G. and SODERHOLM, B. (1963) Acta med. scand. 173, 199. HUTCHINSON, J. (1846) Med-chir, Trans. 29, 137. INTERNATIONAL LABOUR ORGANIZATION (1966) Occupational safety and health series No.6. Geneva. KOTILAINEN, M. and KOTILAINEN, A (1962) Acta med, scand. 171, 569. McKERROW, C. B., McDERMOTT, M. and GILSON, J. C. (1960) Lancet 1, 149. McKERROW, C. B. and ROSSITER, C. E. (1967) in preparation. MOSTYN, E. M., HELLE, S., GEE, J. B. L., BENTIVOGLIO, L. G. and BATES, D. V. (1963) J. appl. Physiol. 18,687. NAIMARK, A and CHERNIACK, R. M. (1960) J. appl. Physiol. 15,377. SALZANO, J., GUNNING, R. V., MASTOPAULO, T. N. and TUTILE, W. W. (1958) J. Am. diet. Ass. 34, 258. TAYLOR, H. L., HENSCHEL, A, BROZEK, J. and KEYS, A. (1949) J. appl, Physiol. 2, 223.