Respirator), Medicine ( 199 i ) 85, 281-284

Reversibility tests in chronic obstructive airways disease: their predictive value with reference to benefit from domiciliary nebuliser therapy C. TEALEt, J. F. J. MORRISON, P. C. JONES* AND M. F. MUERS Pulmonary Function Laboratory, Regional Cardiothoracic Centre, Killingbeck Hospital, Leeds LS14 6 UQ and *Boehringer blgelheim, Bracknell, Berkshire RG12 4 YS, U.K.

The role of short-term tests of reversibility in selecting patients with C O A D for long-term nebuliser therapy is uncertain. In a double-blind placebo-controlled crossover study we have examined the correlation between short-term reversibility and response to a home nebuliser. We studied 20 patients with severe C O A D (mean age 66, mean FEVj 0.81 l) and little reversibility ( < 2 0 % increase in FEV~ post-inhaled salbutamol 200/zg and < 2 5 % increase in peak expiratory flow rate, PEFR, on oral steroids). PEFR, spirometry, lung volumes and airways conductance were recorded before and l h after a mixture ofnebulised ipratropium 0.5 mg and fenoterol 1.25 mg. Patients then recorded twice-daily P E F R at home while they received nebulised ipratropium plus fenoterol, or saline placebo, four times a day for three week blocks using a double-blind cross over protocol. Mean P E F R on home nebuliser rose from 1641 m - ~(placebo) to 196 1m - ~(ipratropium plus fcnoterol), paired t-test P = 0.000 I. Correlation coefficients between short-term response for PEFR, spirometry and lung volumes, and improvement in home P E F R on nebulised ipratropium plus fenoterol, were all poor ( R = -0.37-0.35, P = 0.83-0. l 1). We conclude that in severe COAD, reversibility tests of PEFR, spirometry and lung volumes do not correlate with response to a home nebuliser. Home measurements of P E F R are probably the best objective method of assessing response to a home nebuliser in such patients.

Introduction

Methods

Patients with chronic obstructive airways disease (COAD) may be severely disabled and can present a considerable management problem. Response to standard doses of bronchodilators is often poor, although increasing doses may produce further bronchodilatation (1,2) and we have previously shown that patients with relatively fixed C O A D can improve on regular nebulised bronchodilators (3). Widespread use of such therapy has led to a 'nebuliser epidemic' (4) raising concerns over side effects (5), cost (6) and the possible development of tolerance (7). These problems emphasize the need for objective methods to identify those likely to benefit from a home nebuliser. Laboratory tests of short-term reversibility have been advocated (8), but recent work noted the limitations of short-term reversil~ility tests of peak flow in predicting long-term response (9). We have further analysed the results of our previous study (3) to determine the value of a range of tests of short-term reversibility in predicting response to domiciliary nebuliser therapy in patients with severe steroid resistant COAD.

We studied 20 patients with severe and relatively unresponsive C O A D who fulfilled the following criteria: (l) over 40 years of age; (2) FEV I < 5 0 % predicted; (3) FEV~/FVC < 6 0 % ; (4) symptoms of breathlessness for more than 2 yr; (5) less than 20% improvement in FEV~ after 200/zg salbutamol or 360/zg fenoterol by inhaler; and (6) failure to demonstrate > 25% improvement of P E F R after at least 10 days of prednisolone at least 20 mg daily. Patients performed twice-daily home P E F R measurements, best of three, thoughout the study on rising (before nebulisation) and at 6.00 pm using a mini Wright peak flow meter (Airmed U.K. Ltd). During a 3-week run-in period, normal medication was continued and patients performed three sets of reversibility tests in the laboratory at weekly intervals; reversibility tests were repeated once more 3 weeks after the study was completed. Tests were performed at 2.00pm and always more than 3 h after inhaled bronchodilators. Spirometry was measured with a Vitalograph dry bellows spirometer using the largest of three reproducible curves, P E F R with a mini Wright peak flow meter (best of three), vital capacity and total lung

Received21 December1989and acceptedin revisedform 12February 199i. fTo whom correspondenceshould be addressed. 0954-6111/91/040281 +04 $03.00/0

© 1991 Bailli6reTindall

282

C. Teale et al. Table 1 Reversibility test results. Baseline PEFR, spirometry, lung volumes and airways conductance at week 3 and response to nebulised ipratropium 0.5 mg plus fenoterol 1.25 mg

Parameter Peak flow (1 m -') Forced expiratory volume in I s (I) Forced vital capacity (I) Vital capacity ( I ) Total lung capacity (box) ( 1) Total lung capacity (He) ( I ) Functional residual capacity ( I ) Residual volume (I) Trapped gas volume (1) Airways conductance (1 kPaS)

Baseline (before therapy) 145 (43) 0"81 (0-26) 2-10 (0-83) 2"35 (0"75) 6'47 (1.35) 5"00 (I.44) 4-65 (I-12) 3"82 (1-05) 1'47 (1.17) 0'50 (0.15)

Difference (after-before therapy) 15 (23) 0"12 (0-15) 0"22 (0-33) 0'16 (0'34) --0.25 (0"52) --0'15 (0"54) --0-25 (0"40) --0.33 (0-43) --0.11 (0"73) 0.07 (0"19)

Values in parentheses are SD. capacity (helium) using a helium residual volume apparatus (Warren and Collins) and total lung capacity (box), functional residual capacity, residual volume and airways conductance with a Gould 2800 autobox plethysmograph. All parameters were measured before and 1 h after a mixture of nebulised ipratropium (0.5 mg) and fenoterol (1-25 mg) (Microneb III, Lifecare nebuliser driven by air at 101 min-t). Airways conductance was only measured on 14 patients, the other six being unable to complete the test. Following the run-in, patients were loaned a compressor (Medix traveller, Airmed U.K. Ltd) and a nebuliser (Micro-neb III, Lifecare) and were randomized to receive nebulised ipratropium 0.5 mg plus fenoterol i.25 mg or saline placebo four times a day for three week blocks using a double-blind cross over protocol. Reversibility performed at the third of the three weekly tests was compared with home P E F R response. Week 3 was chosen to minimise any possible learning effect and because it was closest to the period of home nebuliser treatment. The mean of twice-daily recordings of P E F R were used as the best measure of longterm response because they can be performed easily by patients at home and have been shown to be the most sensitive index of response to oral prednisolone in C O A D (10), probably because of the greater number of measurements performed (I 1). The study was approved by the Leeds Eastern Health Authority Ethics Committee and written informed consent obtained from each patient. Since the aim of the study was to identify parameters that may be indicative of long-term response, we have used (Pearson) correlation coefficients. They indicate a relationship between two variables but do not give evidence of causation. The change in P E F R after 3 weeks ofactive nebuliser therapy compared with placebo has

been correlated with short-term reversibility of numerous parameters and, thus, statistical significance should not be attached to P values 15% increase in home PEFR. There was no variability in baseline between the different treatment phases and no drift across the whole 12 weeks of the study. Table 2 shows the correlations between change in PEFR, spirometry, lung volumes and airways conductance following nebulised ipratropium plus fenoterol and improvement in home P E F R on domiciliary nebuliser therapy; the figure shows scatter plots for spirometry and airways conductance. There was a strong correlation for airways conductance (R = 0.82, 95 % confidence interval 0.52-0.94, P < 0.001 ), but all other correlations were much lower (R=0.05-0.37, P = 0-83--0-11). We also examined the effect o f repeating reversibility tests to see if the mean or best of the three weekly tests of reversibility of FEV~ or FVC was

Reversibility tests in chronic obstructive airways disease

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Fig. 1 Reversibility testing in COAD: plots of short-term change in FEV t, FVC and SGAW following nebulised ipratropium plus fenoterol against change in home PEFR on regular nebulised ipratropium plus fenoterol.

a better predictor of long-term response than a single test (see Table 3). However, the mean and best of three reversibility tests for both FEVI and FVC still failed to achieve significance at the 5% level.

Discussion

Our results suggest that in severe steroid resistant, C O A D short-term reversibility tests, with the possible exception of airways conductance, fail to predict long-term response to a home nebuliser. There are few published studies on the role of reversibility tests in predicting response to a home nebuliser and none have examined the range of parameters assessed in this study. O'Driscoll et al. (9) showed a poor correlation between short-term improvement in P E F R following a single nebulised dose of bronchodilator and long-term response to a home nebuliser (9).

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Our results confirm their findings for tests of P E F R and also show that short-term changes in spirometry and lung volumes following nebulised brochodilators fail to predict the long-term response, as assessed by twice-daily measurements of PEFR. The poor correlation between short-term reversibility and long-term response we describe may reflect the poor reproducibility of reversibility tests in these patients. Nisar et al. (12) demonstrated that of four tests of reversibility to nebulised salbutamol in patients with C O A D "a clear pattern of response was seen in less than 50%'. Tweeddale et al. (13) suggested that the increase in FEV~ required to exclude natural variability with 95% confidence was 0.16 I. The majority of our patients failed to achieve such a response with a mean increase in FEV] of 0.121. However, independent analysis of the responses of those six patients who showed a > 0.161 increase in FEV~ post-nebulisation, which must be interpreted with caution because of the small numbers, still showed a poor correlation between short-term improvement in FEV~ following nebulisation and increase in home P E F R on nebulised ipratropium plus fenoterol (R = 0.05, P = 0.32). The correlation between short-term reversibility of airways conductance and response to home nebuliser is of interest. It may reflect a chance association given the large number of parameters screened although the R value of 0-82 (P

Reversibility tests in chronic obstructive airways disease: their predictive value with reference to benefit from domiciliary nebuliser therapy.

The role of short-term tests of reversibility in selecting patients with COAD for long-term nebuliser therapy is uncertain. In a double-blind placebo-...
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