Response to Inhaled Bronchodilators in COPD

Response to Inhaled Bronchodilators in COPO* N. R. Anthonisen, M.D.;t E. C. Wright;+ and the IPPB Trial Group§

connection with the recently completed clinical I ntrial of intermittent positive pressure breathing

(IPPB),1 we accumulated and analyzed a great deal of data concerning bronchodilator responses in COPD.2 In the course of the trial, 985 patients with COPO were recruited and followed closely for approximately three years. To gain entry to the trial, patients were required to have a clinical diagnosis of COPD, not asthma, to have an FEV l <60 percent predicted, an FEV/FVC <60 percent and TLC ~80 percent predicted, and to be clinically stable. Patients who were hypoxemic (Pa02 s 55 mm Hg) or who had other serious diseases were excluded. Among the 985 patients who participated in the study, there were literally hundreds with severe, moderate and relatively mild airflow limitation: except for patients who were hypoxemic on entry, the full spectrum of COPO severity was studied. Patients were treated in a standard way, employing inhaled beta agonists and oral theophylline. Antibiotics, steroids, O2 and diuretics were used according to prearranged indications. 1 At yearly intervals, patients underwent detailed lung function testing, including measurements of diffusing capacity (Dco), airwayresistance (Raw), lung volumes, blood gases and exercise tolerance, and also were evaluated in terms of symptoms. At three-month intervals the patients underwent spirometry with measurement of FEV1 before and after 250 ...,g of isoproterenol were inhaled. Before these measurements were made, patients were asked to abstain from inhaled bronchodilator for six hours and from oral theophylline for at least 12 hours, and at the time of testing they were questioned to ascertain whether they had done so. Bronchodilator response was assessed in terms of changes in FEV l and Raw The latter showed a great deal of scatter and was therefore dropped from the

analysis. Changes in FEV1 were assessed in two ways. "Relative" response was defined as the post-isoproterenol FEV l taken as a percentage of that measured before isoproterenol. "Absolute" response was defined as the algebraic difference between postisoproterenol and pre-isoproterenol FEV l taken as a percentage of the predicted normal value. When patients admitted to use of inhaled bronchodilator medications within six hours prior to testing, responses were reduced and these tests were therefore dropped from analysis. Interestingly, responses were not related to blood theophylline levels measured within a month of the assessment of bronchodilator response. This may indicate that the patients, in fact, did abstain from theophylline use before testing, or that the mechanisms of theophylline and isoproterenol responses were different, a somewhat less likely possibility. Figures 1and 2 show relative and absolute responses in the series as a whole measured at baseline. The average relative response was 115 percent, and more than 30 percent of the patients showed responses of120 % Patients 20

·Supported by contracts No I-HR-72901, 72902, 72903, 72904, 72905, 72906 from the Division of Lung Diseases, National Heart Lung and Blood Institute, National Institutes of Health, and MRC

ofC8nada.

tRespiratory Section, Department of Medicine, Health Sciences Center, University of Manitoba, Wmnipeg, Canada. *Biostatistics Center, George Washington University, Bethesda, Maryland. IJ. E. Hod~, M.D. St Helena, Califom~ ~ C. Hopewell, M.D., San FranClSCO; D. C. Levin, Oklahoma City; and :e M. Stevens, M.D., Houston

38S

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FIGURE 1. Frequency distribution for relative bronchodilator response (abscissa), measured at baseline. InhaledBtonchodIIators In COPD (AnthonIsen et 81)

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FIGURE 3. Relationship between baseline FEV 1 (abscissa, in %

predicted), andbaseline bronchodilator response. Relative response

Post J=EV 1 -Pre FEV 1 (% Pred) FIGURE 2. Frequency distribution for absolute bronchodilator response (abscissa), measured at baseline.

percent or greaten The absolute response averaged 5 precent of the predicted normal FEV. (above .15 L) with about 15 percent of the patients having responses exceeding 10percent of the normal FEV l (about. 30 L). Thus, the vast majority of the patients demonstrated a useful bronchodilator response. These responses are somewhat larger than those observed in other studies ofCOPD, which may be ascribable to the fact that we exclude subjects who had used inhaled beta agonists up to six hours before testing. It should also be noted that Figures 1 and 2 probably do not show maximal responses; we used only two puffsofisoproterenol from metered dose inhalers. Had larger doses been used, responses would almost certainly have been larger, Given the responses shown in Figures 1 and 2, which were acquired in COPD patients thought not to have asthma, it would be very difficultto separate asthmatic patients from COPD patients on the basis of bronchodilator response. Half of our patients showed a 15 percent increase in FEV., which has been cited as an indicator of asthma or "asthmatic bronchitis." Figure 3 relates baseline bronchodilator response to baseline values of prebronchodilator FEVl • Relative response was closely and inversely correlated with baseline FEV.: the lower the FEVl the greater the percentage increase with bronchodilator; Part of the reason for this is algebraic; in a patient with an initial FEV. of 0.6 L, 15-20 percent increases with bronchodilator are no greater than the random error of the measurement of FEV l • On the other hand (Fig 3), absolute responses were directly correlated with the baseline FEV.: patients with large values of FEV l tended to have large absolute responses. This rela-

is left ordinate and closed symbols, and right abscissa and open symbols are absolute response. Each datum is the mean result of at least 50 patients.

tionship was Significant, though not as tight as that between FEV l and relative response. It is clear from Figure 3 that studies assessing determinants (including drugs) of bronchodilator response need either to examine more than one kind of response or to standardize for baseline FEV l • Bronchodilator response at baseline correlated poorly with other features of the disease. This was examined by stepwise regression, first taking baseline FEV. into account. Response did not relate to blood gases, evidence of emphysema (TLC, Dco), age, sex, or dyspnea. Weak, but significant positive correlations were found with symptomatic wheezing and maximum exercise tolerance, and there was a negative correlation with smoking habit. These correlations applied to both absolute and relative responses, and so appear genuine. Patients with a given level of prebronchodilator FEV l and relatively large bronchodilator responses complained more of wheeze and had a relatively wellpreserved exercise tolerance. Presumably, once FEV l had been considered, wheeze and exercise tolerance reflected lability of airways obstruction. The negative correlation with smoking history could be interpreted as indicating that heavy smoking reduces bronchodilator response, or alternatively that "reactivity" as expressed by bronchodilator response is additive to smoking in depressing the FEV b so that in a group of patients with the same reduction in FEVl , those with little reactivity would be heavy smokers, and vice versa. It should be emphasized, however, that these correlations were very weak and together explained only 5-8 percent of the total variation in bronchodilator response after allowing for the effect of the initial FEV l • Patients with large bronchodilator responses showed increased variation of FEVl during follow-up. This was CHEST I 91 I 5 I MAY. 1987 I Supplement

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FIGURE 4. Bronchodilator response and variability of FEV1 with time, represented by DEV FEV1 on the ordinates. Relative bronchodilator response is closed symbols and lower abscissa, while absolute response is the open symbols and upper abscissa. Brackets enclose 1 SEM.

the case for both absolute and relative responses (Fig 4) and was particularly notable in patients with the most dramatic bronchodilator responses. Presumably, both variation in FEVl with time and bronchodilator response represent lability of airways obstruction. Perhaps the most interesting single finding revealed by our. analyses was that both relative and absolute bronchodilator responses were inversely correlated with rate of decline ofFEVl (Fig 5). Patients with small responses tended to decline rapidly and the reverse was true of those with large responses; indeed, those with the largest bronchodilator responses declined less than half as fast as did others (Fig 5). This finding applied both to our series as a whole and to those patients with the least airways obstruction as indicated by initial values of FEV l between 49 and 60 percent predicted normal. This appears to indicate that patients with the greatest airways reactivity had a relatively slow decline in lung function, and conflicts with several well-known studies which have indicated the reverse.P" These studies examined relatively healthy individuals, but this does not explain the discrepancy in results, since we found a slow decline in patients with well-preserved and comparable values of FEV l • Some of the differences between our results and those of others may reside in analytic methods, but the most obvious potential reason for the conflict is the fact that our patients received regular bronchodilator therapy, while this was not the case in other studies.P" This suggests that in bronchodilator responsive, reactive patients, bronchodilator therapy is of more than symptomatic benefit, changing the course of disease for the better, This is an exciting hypothesis that needs to be tested. Bronchodilator response itself showed considerable variability with time. On average, relative response did not change during follow-up, and absolute re38S

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FIGURE 5. Bronchodilator response and yearly decline in FEV1, represented by FEV1 on the ordinates. Relative bronchodilator response is the closed symbols and bottom abscissa, and absolute response, the open symbols and upper abscissa. Brackets enclose 1 SEM.

sponse declined very slightly. While the latter finding might be interpreted as evidence of tachyphylaxis, it more likely was related to the gradual decline in FEVl observed in our patients: as FEV l fell, so did the absolute increase in FEV l with bronchodilator However, the most important feature emerging from serial measurements of bronchodilator response was its variability. This is best illustrated by examining results in patients who were on the initial examination either unresponsive-relative response <110 percent-or responsive-relative response > liS percent. At any given follow-up test, 30 percent of patients who were initially unresponsive showed responses greater than liS percent, and after seven follow-uptests, 68 percent of these patients had demonstrated at least one response of greater than liS percent. When responsive patients were examined, the results were stmilan Some 30-40 percent of patients who initially had relative responses > liS percent showed a response <110 percent on any single test, and after seven tests, 70 percent of the group had been unresponsive on at least one occasion. It was impossible to separate variations of bronchodilator response from variation in FEVl and it could not be established that the latter was not simply due to measurement errol: Whatever their cause, the variability of bronchodilator response that we observed makes an important point: the degree of a patient's responsiveness cannot be established with certainty on the basis of a single testing session using the usual dose of bronchodilator We should not make therapeutic decisions such as whether or not to administer bronchodilator therapy on the basis of such data. InhaledBronchodilators In COPD(Anthon/sen et 81)

REFERENCES 1 Intermittent Positive Pressure Breathing'Iiial Group. Intermittent positive pressure breathing therapy of chronic obstructive pulmonary disease. Ann Intern Med 1983;99:612-20 2 Anthonisen NR, Wright EC, IPPB 1iial Group. Bronchodilator response in COPD. Am Rev Respir Dis (in press) 3 Barter CE, Campbell AH, Tandon MK. Factors affecting the decline of FEV 1 in chronic bronchitis. Aust NZ J Med 1974;

4:339-45 4 Barter CE, Campbell AH. Relationship of constitutional factors and cigarette smoking to decrease in I-second forced expiratory volume. Am Rev Respir Dis 1976; 113:305-14 5 VollmerWM, Johnson LR, Buist AS. Relationship of response to a bronchodilator and decline in forced expiratory volume in one second in population studies. Am Rev Respir Dis 1985; 132: 1186-93

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