Abstract
Pulmonary function methods which are able to detect small pharmacological effects may be useful for assessing the full dose–response curve of bronchodilatators. We compared the ability of impulse oscillometry (R5, R20, X5, RF), plethysmography (sGaw) and spirometry [forced expiratory volume in 1 s (FEV1), maximal mid expiratory flow rate (MMEF)] to measure the dose–response effects of salbutamol in 12 healthy subjects, 12 mild asthmatics (mean FEV1 96% predicted) and 12 moderate asthmatics (mean FEV1 63% predicted). The techniques were performed twice to assess variability. Then salbutamol 10, 20, 100, 200 and 800 µg was administered. The sensitivity of the methods were compared by determining the lowest dose that caused changes greater than variability. In healthy subjects significant changes (p≤ 0.05) were observed only in FEV1 (4.1%) and MMEF (14.6%) at 100 µg and sGaw (25.6%) and R20 (8.3%) at 200 µg. In mild asthmatics significant changes were observed in sGaw (15.9%) at 10 µg, X5 (23%), RF (20.3%) and MMEF (15.7%) at 20 µg, R5 (13.9%) and R20 (9.4%) at 100 µg and FEV1 (7.1%) at 200 µg. All measurements except R20 demonstrated significant changes at 10 µg in moderate asthmatics. The most sensitive test for assessing bronchodilatation is different in healthy subjects and asthmatics, and varies with severity of airflow obstruction.
Keywords: lung function tests, reversibility technique
Introduction
New bronchodilatator treatments for asthma are tested initially in healthy subjects (Phase 1 studies) prior to clinical trials involving asthmatics with a range of severities. Bronchodilatation in healthy volunteers and asthma clinical trials is usually assessed by spirometry, which measures expiratory flow rates and volumes. A widely used alternative is the measurement of airway conductance using body plethysmography. While bronchodilatation can also be measured using the impulse oscillation (IOS) technique, its use in clinical trials has been limited [1–3]. A potential advantage of this technique is that it assesses different components of respiratory impedence; the measurements obtained include central and peripheral airway resistance (R20 and R5, respectively) as well as pulmonary reactance (Xrs), which is a function of lung compliance and inertiance [4]. As inertiance is negligible at the lower frequencies used during IOS measurements, Xrs can be used to assess the elastic properties of the lung. The use of IOS in clinical practice is increasing, particularly for the diagnosis of asthma in children [5–7]. However, the value of this technique for investigating the effects of novel treatments for asthma in clinical trials has not been fully assessed.
The evaluation of novel drugs during clinical trials involves assessment of the dose–response curve. This allows the doses for use in clinical practice to be determined. However, there have been no studies comparing the ability of IOS, spirometry and body plethysmography to assess the dose–response effects of bronchodilatator drugs. Although spirometry is well established in clinical practice for measuring bronchodilatation after a standard dose of a short-acting bronchodilatator such as salbutamol, its ability to detect smaller changes in airway tone has not been directly compared with both IOS and body plethysmography. The assessment of small changes in lung physiology caused by novel drugs may be important in clinical trials, e.g. when measuring the duration of action of novel long-acting bronchodilatators, or assessing the effects of drugs that act through novel mechanisms and so may be used in conjunction with β2-receptor agonists or anticholinergic agents.
The ability of pulmonary function methods to detect dose–response effects, including small changes in airway tone, is dependent on both the variability and the sensitivity of the methods [8]. These parameters may be different in healthy subjects compared with asthmatics. Therefore, in healthy subjects and in patients with mild and moderate asthma this study set out to determine (i) the variability of spirometry, plethysmography and IOS, (ii) the dose–response effects of salbutamol measured using these three techniques, and (iii) the sensitivity of the methods by calculating the dose of salbutamol that caused effects greater than method variability. Thus we were able to compare the sensitivity of spirometry, plethysmography and IOS in order to determine the most appropriate measurements in clinical trials of bronchodilatators in healthy subjects and asthmatics.
Methods
Subjects
Thirty-six subjects (demography shown in Table 1) participated: 12 healthy subjects with no significant medical history and taking no medications, 12 mild asthmatics [forced expiratory volume in 1 s (FEV1) >80% predicted] and 12 moderate asthmatics (FEV1 <80% predicted). Asthma was diagnosed on clinical history plus historical evidence of typical asthma physiology; peak expiratory flow variability, FEV1 reversibility >12% or bronchial hyperresponsiveness. None of the subjects satisfied the GOLD criteria for a diagnosis of chronic obstructive pulmonary disease (COPD) [9]. Written informed consent was obtained and the local ethics committee approved the study.
Table 1.
Subject demographics
| Healthy volunteers | Mild asthma | Moderate asthma | ||||
|---|---|---|---|---|---|---|
| Age (range)* | 40.5 (27–66) | 46.8 (25–64) | 40.8 (21–69) | |||
| Female† | 7 (58%) | (75%) | (75%) | |||
| FEV1% predicted* | 105 (92–115) | 96 (80–117) | 63 (49–77) | |||
| Ex-smoker‡ | 3 (40.5) | 3 (16) | 3 (4) | |||
| Current smoker‡ | 2 (1.7) | 0 | 0 | |||
| Steroid use† | ||||||
| None | 12 (100%) | 1 (8%) | 0 | |||
| <400 µg BDP | 6 (50%) | 1 (8%) | ||||
| >400 µg BDP | 5 (42%) | 11 (92%) | ||||
| Long-acting β2-agonist† | 0 | 0 | 5 (42%) | |||
BDP, Beclomethasone dipropionate or equivalent.
Mean (range).
Number of subjects (%).
Number of subjects (mean pack year smoking history in smoking subjects).
Study design
On day 1, pulmonary function was assessed by spirometry, plethysmography and IOS (Test 1). Pulmonary function was repeated 30 min later (Test 2). On day 2 (1 week later) measurements were repeated at the same time of day (Test 3). Each lung function test was performed three times on all occasions. After Test 3 salbutamol was administered in ascending doses of 10, 20, 100, 200 and 800 µg separated by 30-min intervals. Pulmonary function was performed 15 min after each dose. Short- and long-acting bronchodilatators were withheld for 6 and 12 h, respectively, prior to study days in accordance with their duration of action [10].
Pulmonary function
Pulmonary function tests were always performed in the same order; first IOS, followed by body plethysmography and then spirometry. The deep inspiration required for spirometry may cause a temporary alteration in bronchial tone [11]. We therefore performed resistance measures prior to spirometry. For IOS (Masterscreen IOS; Erich Jaeger, Hoechberg, Germany) subjects supported their cheeks to reduce upper airway shunting while impulses were applied during tidal breathing for 30 s. R5 and R20 (respiratory resistance at 5 and 20 Hz, respectively), X5 (reactance at 5 Hz) and RF (resonant frequency) were recorded. sGaw was measured in a constant volume plethysmograph (Sensormedics Vmax 6200). Maximum expiratory flow volume measurements; FEV1 and MMEF (maximal mid expiratory flow rate) were performed using the spirometry system on the Masterscreen. A full explanation and training in the performance of each lung function test were given to each subject prior to the study. All tests were performed by the same experienced operator. Salbutamol (Ventolin nebules; Allen and Hanburys, Greenford, UK) was administered via a dosimeter (Mefar, Medicali, Brescia, Italy) calibrated to deliver 10 µl per inhalation; 1 mg ml−1 nebules were used to administer 10- and 20-µg doses while 2 mg ml−1 nebules were used for the subsequent doses with the number of inhalations altered to deliver the required doses. The dose levels quoted are the ‘potential’ lung doses, rather than the actual delivered dose.
Statistical methods
A sample size of 12 subjects per group was chosen as it allows power calculations for future clinical trials of bronchodilatator drugs to be performed with 90% power using the within-subject standard deviation (SD) observed. These estimates will have at least 73% power if the true within-volunteer SD is 25% larger than observed in the present study.
The within-test variability was defined as the variation due to the method during three repeated measurements at the same time point. This was assessed by the coefficient of variation (CV), the SD/mean, of the three readings. The mean of these three readings was used for all further analysis. The within-subject variation was assessed both (i) within day (comparison of Tests 1 and 2) and (ii) between day (comparison of Tests 1 and 3) using the single determination SD [12] to calculate the CV. Measurements after each dose of salbutamol were compared with the baseline measurement on the same day (i.e. Test 3). The physiological changes observed were compared with within-day variability (i.e. the percent difference between Tests 1 and 2) using a paired Student's t-test. This allowed significant physiological changes greater than within-day variability to be identified. For clarity, the dose levels that caused significant changes are presented. However, prior doses will have caused a carry-over effect, e.g. at the 100-µg dose level the cumulative dose is 130 µg.
Results
Variability of spirometry, plethysmography and IOS
Using CV to assess repeatability (see Table 2), FEV1 was the least variable measurement in healthy subjects and asthmatics. The mean FEV1 values are shown, although in clinical practice the highest of three tests is usually recorded. However, using the highest reading gave similar within- and between-day variability (data not shown). FEV1 was more variable in asthmatics compared with healthy volunteers. The greatest variability was observed in moderate asthmatics as within-test, within-day and particularly between-day FEV1 variability was greater in this group compared with mild asthmatics. MMEF, RF, R20 and R5 also had greater variability in asthmatics compared with healthy subjects. However, X5 and sGaw were the most variable measurements in healthy subjects and had similarly high variability in asthmatics.
Table 2.
Variability of plethysmography, impulse oscillation (IOS) and spirometry
a.Healthy volunteers
| Day 1 | Day 2 | Coefficient of variation (%) | ||||
|---|---|---|---|---|---|---|
| Test 1 Mean (SD) | Test 2 Mean (SD) | Test 3 Mean (SD) | Within test | Within day | Between day | |
| sGaw, s−1 kPa−1 | 1.97 | 1.9 | 1.88 | 9.2 | 18.8 | 10.5 |
| (0.91) | (0.62) | (0.73) | ||||
| R5, kPa l−1.s | 0.29 | 0.29 | 0.29 | 6 | 9.4 | 9.1 |
| (0.07) | (0.08) | (0.08) | ||||
| R20, kPa l−1.s | 0.29 | 0.29 | 0.29 | 5.5 | 6.6 | 8.0 |
| (0.07) | (0.08) | (0.09) | ||||
| X5, kPa l−1.s | 0.09 | 0.09 | 0.1 | 11 | 16.7 | 17.1 |
| (0.03) | (0.05) | (0.04) | ||||
| RF, Hz | 8.95 | 8.99 | 9.13 | 3.9 | 5.8 | 5.8 |
| (0.71) | (0.85) | (0.82) | ||||
| FEV1, l | 3.48 | 3.53 | 3.49 | 1.8 | 1.3 | 2.0 |
| (0.75) | (0.71) | (0.71) | ||||
| MMEF, l s−1 | 3.06 | 3.18 | 3.13 | 6.4 | 3.68 | 5.0 |
| (0.89) | (0.91) | (0.89) | ||||
Table 2b.
b. Mild asthma
| Day 1 | Day 2 | Coefficient of variation (%) | ||||
|---|---|---|---|---|---|---|
| Test 1 Mean (SD) | Test 2 Mean (SD) | Test 3 Mean (SD) | Within test | Within day | Between day | |
| sGaw, s−1 kPa−1 | 1.17 | 1.16 | 1.22 | 8.6 | 10.7 | 12.3 |
| (0.35) | (0.31) | (0.41) | ||||
| R5, kPa l−1.s | 0.45 | 0.45 | 0.44 | 6 | 7.9 | 10.4 |
| (0.26) | (0.23) | (0.24) | ||||
| R20, kPa l−1.s | 0.36 | 0.36 | 0.35 | 5.2 | 11.2 | 12.7 |
| (0.17) | (0.14) | (0.15) | ||||
| X5, kPa l−1.s | 0.14 | 0.15 | 0.14 | 12.1 | 9.2 | 13.9 |
| (0.07) | (0.08) | (0.08) | ||||
| RF, Hz | 16.49 | 16.81 | 17 | 5.4 | 6.6 | 20.6 |
| (7.8) | (8.02) | (8.44) | ||||
| FEV1, l | 2.65 | 2.68 | 2.7 | 2.1 | 2.9 | 3.5 |
| (0.54) | (0.58) | (0.6) | ||||
| MMEF, l s−1 | 1.83 | 1.82 | 1.83 | 8.2 | 8.0 | 9.5 |
| (0.54) | (0.57) | (0.53) | ||||
Table 2c.
c. Moderate asthma
| Day 1 | Day 2 | Coefficient of variation (%) | |||||
|---|---|---|---|---|---|---|---|
| Test 1 Mean (SD) | Test 2 Mean (SD) | Test 3 Mean (SD) | Within test | Within day | Between day | ||
| sGaw, s−1 kPa−1 | 0.67 | 0.71 | 0.75 | 9.6 | 9.1 | 17.0 | |
| (0.51) | (0.49) | (0.53) | |||||
| R5, kPa l−1.s | 0.67 | 0.65 | 0.63 | 6.9 | 13.5 | 13.1 | |
| (0.21) | (0.14) | (0.19) | |||||
| R20, kPa l−1.s | 0.47 | 0.44 | 0.44 | 5.7 | 10.1 | 11.8 | |
| (0.13) | (0.08) | (0.12) | |||||
| X5, kPa l−1.s | 0.28 | 0.28 | 0.28 | 9.5 | 14.3 | 15.5 | |
| (0.15) | (0.13) | (0.16) | |||||
| RF, Hz | 24.71 | 24.64 | 24.31 | 7.2 | 13.6 | 14.9 | |
| (5.52) | (5.18) | (6.5) | |||||
| FEV1, l | 1.89 | 1.9 | 1.94 | 3 | 3.3 | 11.6 | |
| (0.55) | (0.52) | (0.55) | |||||
| MMEF, l s−1 | 1.05 | 1.04 | 1.11 | 10.1 | 4.7 | 15.6 | |
| (0.73) | (0.72) | (0.71) | |||||
Measurement of the dose–response effects of salbutamol
The physiological changes caused by each dose of salbutamol are shown in Table 3, with statistically significant changes defined as those greater than within-day variability.
Table 3.
Salbutamol dose–response
| Dose (µg) | 10 | 20 | 100 | 200 | 800 | Within-day change |
|---|---|---|---|---|---|---|
| sGaw | 4.1 | 12.0 | 20.9 | 25.6* | 26.4* | 1.1 |
| (− 5.4, 13.6) | (0.9, 23.1) | (7.3, 34.5) | (12.3, 38.9) | (11.5, 41.3) | (−11.4, 13.6) | |
| R5 | 1.2 | 1.4 | 1.6 | 5.9 | 10.6 | 0.9 |
| (− 5.2, 7.6) | (− 6.5, 9.3) | (− 6.6, 9.8) | (2.3, 9.5) | (5.4, 15.8) | (−5.8, 7.6) | |
| R20 | 1.5 | 1.0 | 2.1 | 8.3* | 12.7* | 0.8 |
| (− 2.7, 5.7) | (− 5.7, 7.7) | (− 5.2, 9.4) | (5.2, 11.4) | (8.4, 17) | (−4.2, 5.8) | |
| X5 | 7.7 | 9.2 | 14.3 | 13.5 | 17.4 | 2.5 |
| (− 0.2, 15.6) | (3.4, 10.5) | (5.4, 23.2) | (0, 27) | (7.5, 27.3) | (−8.9, 13.9) | |
| RF | 3.3 | 4.3 | 4.9 | 4.4 | 4.5 | 0.7 |
| (0.7, 5.9) | (1.4, 7.2) | (1.4, 8.3) | (0.4, 8.4) | (0.4, 8.6) | (−3.7, 5.1) | |
| FEV1 | 3.7 | 2.34 | 4.14* | 3.79* | 4.65* | 1.9 |
| (− 0.6, 7) | (1.1, 3.5) | (2.6, 5.6) | (2.1, 5.5) | (3, 6.4) | (0.7, 3.1) | |
| MMEF | 8.7 | 9.5 | 14.6* | 15.8* | 19.2* | 4 |
| (4.6, 12.8) | (5.1, 13.9) | (8.2, 21) | (10.8, 20.8) | (11.6, 26.8) | (1.2, 6.8) |
Table 3b.
b.Mild asthma
| Dose (µg) | 10 | 20 | 100 | 200 | 800 | Within-day change |
|---|---|---|---|---|---|---|
| sGaw | 15.9* | 28.1* | 44.7* | 53.9* | 58.2* | 0.4 |
| (3.5, 28.3) | (11.2, 45) | (22.9, 66.5) | (27.1, 80.7) | (30.4, 86) | (−7.3, 8.1) | |
| R5 | 1.8 | 5.7 | 13.9* | 18.8* | 18.1* | −3.6 |
| (−8.3, 11.9) | (− 4.5, 15.9) | (2.4, 25.4) | (8.3, 29.3) | (7.3, 18.9) | (−12.2, 5) | |
| R20 | −0.3 | 0.3 | 9.4* | 14.6* | 14.4* | −4.7 |
| (−8.3, 7.7) | (−8.9, 9.5) | (−0.5, 19.3) | (6.4, 22.8) | (5.6, 23.2) | (−14.4, 5) | |
| X5 | 10.8 | 23* | 19.1* | 20.8* | 27.2* | −2.0 |
| (−5.6, 27.2) | (7.7, 38.3) | (3.5, 34.7) | (4.4, 37.2) | (14.2, 40.2) | (−10.7, 6.7) | |
| RF | 13.6 | 20.3* | 25.3* | 26.8* | 27.1* | 1.7 |
| (−0.2, 27.4) | (5.4, 35.2) | (10.2, 40.4) | (10.6, 43) | (11.2, 43) | (−4.1, 7.5) | |
| FEV1 | 2.6 | 4.0 | 5.3 | 7.1* | 7.9* | 0.9 |
| (0.2, 5) | (1, 7) | (1.3, 9.3) | (3.1, 11.1) | (3.6, 12.2) | (−1.5, 3.3) | |
| MMEF | 8.3 | 15.7* | 16.8* | 26.6* | 29.8* | −0.3 |
| (1.2, 15.4) | (9.1, 22.3) | (6.7, 26.9) | (16.8, 36.4) | (20, 39.6) | (−7.3, 7.9) |
Table 3c.
c.Moderate asthma
| Dose (µg) | 10 | 20 | 100 | 200 | 800 | Within-day change |
|---|---|---|---|---|---|---|
| sGaw | 28.8* | 46.8* | 68.5* | 82.5* | 100.9* | 9.0 |
| (7.6, 50) | (17.4, 76.2) | (28.5, 109) | (33.5, 131.5) | (38.4, 163.4) | (−4.5, 22.5) | |
| R5 | 11.4* | 17.3* | 26.3* | 30* | 30.8* | −0.1 |
| (5.4, 17.4) | (10.2, 24.4) | (19.2, 33.4) | (22.3, 37.7) | (21.9, 39.7) | (−10.2, 10) | |
| R20 | 5.1 | 8.9 | 16.1* | 16.3* | 21* | 3.4 |
| (−1.1, 11.3) | (2.3, 15.5) | (10.6, 21.6) | (7.5, 25.1) | (15.2, 26.8) | (−2.8, 9.6) | |
| X5 | 21* | 31.7* | 39.1* | 41.5* | 42* | −1.6 |
| (14.4, 27.6) | (22.1, 41.3) | (29, 49.2) | (30.1, 52.9) | (29.5, 54.5) | (−11.9, 8.7) | |
| RF | 17.3* | 23.7* | 33.5* | 36* | 37.2* | 1.5 |
| (9.2, 25.4) | (15.8, 31.6) | (25.1, 41.9) | (25.1, 46.9) | (26.8, 47.6) | (−8.6, 11.6) | |
| FEV1 | 9.7* | 16.9* | 25.3* | 28.1* | 32.5* | 0.9 |
| (1.4, 18) | (6.3, 27.5) | (9.9, 40.7) | (11.7, 44.5) | (13.5, 51.5) | (−1.7, 3.5) | |
| MMEF | 12.5* | 25.4* | 36.5* | 45.6* | 52.8* | −0.3 |
| (0.8, 24.2) | (9, 41.8) | (20.2, 52.8) | (25.2, 66) | (23.9, 81.7) | (−4.3, 3.7) |
p ≤ 0.05 denotes dose at which significant change compared with variability occurred. Data are mean percentage change (95% confidence interval).
Sensitivity of the measurements
In healthy subjects spirometry (FEV1 and MMEF) was the most sensitive measurement with significant salbutamol effects detected at 100 µg. sGaw was less sensitive with significant effects observed only after the 200-µg dose. Using IOS, only R20 detected significant salbutamol effects (at 200 µg). In mild asthmatics, only plethysmography demonstrated significant bronchodilatation after the lowest dose of salbutamol (10 µg). This method was therefore the most sensitive in mild asthma. After 20 µg, bronchodilatation was also detected by MMEF, X5 and RF, and after 100 µg by R20 and R5. FEV1 was the least sensitive measurement as it did not detect significant salbutamol effects until 200 µg, although statistical significance was almost reached after 100 µg (p = 0.08). In moderate asthmatics, all the pulmonary function measurements (except R20), showed similar sensitivity as significant effects were observed after the lowest dose of salbutamol (10 µg).
Magnitude of change in measurements
In healthy subjects, the percentage changes in FEV1, sGaw and R20 were similar after 10 µg salbutamol. However, after the 800-µg dose the percentage change in R20 was over twofold greater than FEV1, while sGaw was over fivefold greater. In mild asthmatics, the relationship between the magnitude of change in FEV1 and IOS resistance measurements was similar to those observed in healthy volunteers; the changes in R20 and R5 were similar to FEV1 after the 10-µg dose, but over two-fold greater after 800 µg. However, the relationship between sGaw and FEV1 was different compared with healthy volunteers; the change in sGaw was over fivefold greater after the 10-µg dose, and over sevenfold greater after the 800-µg dose.
In moderate asthmatics the changes in R5 and FEV1 were similar, with R20 being slightly lower. The changes in sGaw were approximately threefold greater than FEV1 at all doses. These results in moderate asthmatics were different from those in mild asthmatics and healthy subjects. The relationship between changes in MMEF and FEV1 also differed between groups; in healthy subjects and mild asthmatics MMEF changes were approximately four- to fivefold greater than FEV1. However, in moderate asthmatics MMEF changes were less than twofold greater than FEV1.
Discussion
The novel aspects of this study are that we have (i) directly compared the ability of spirometry, plethysmography and IOS to detect dose–response effects, (ii) taken into account method variability in determining the most sensitive method, and (iii) assessed whether the sensitivity of the methods varies between healthy subjects and asthmatics, and with the severity of airflow obstruction. Previous studies assessing bronchodilatation have shown that the greatest percentage change is observed using sGaw, leading to the conclusion that this is the most sensitive method [13–16]. However, these studies have limitations. First, variability has not always been taken into consideration when assessing the physiological changes caused by a drug [14, 15]. Second, the majority of the studies have only used one drug dose (usually a standard clinical dose) [13–15]. Consequently, the utility of spirometry, plethysmography and IOS to detect small changes while taking into account method variation, which is critical when assessing the full dose–response curve, is not known. Third, pulmonary function methods have been compared in mixed groups of COPD and asthma patients and healthy volunteers [13, 14] and we have shown that the sensitivity of these methods to detect change varies with the presence and the severity of airflow obstruction. Our study overcomes all of these limitations.
We initially assessed the variability of spirometry, plethysmography and IOS. It is known that plethysmography is more variable than spirometry, and that FEV1 is a less variable spirometric measurement compared with mid-expiratory flow rate readings such as MMEF [13, 17–19]. However, we could find only two previous studies comparing spirometry and plethysmography with oscillation techniques [13, 14], which both showed that sGaw was the most variable test, followed by oscillometry, with spirometry the least variable. Our findings were similar for all parameters of variability (within test, within day and between day); MMEF, sGaw and IOS measurements were more variable than FEV1 in both healthy subjects and asthmatics. We also demonstrated that the variability of FEV1, MMEF, RF, R20 and R5 was increased in asthmatics compared with healthy subjects. However, sGaw and X5 showed the highest variability in healthy subjects, which was not increased further in asthmatics. These results indicate that the variability of some measurements is altered by the presence of airflow obstruction, presumably due to increased natural biological variation.
In healthy volunteers we found that spirometry measurements (FEV1 and MMEF) were the most sensitive. There was a greater magnitude of change in sGaw, but this was less sensitive than spirometry because of greater variability. The sensitivity of sGaw to detect bronchodilatation in healthy subjects can be improved by decreasing method variability; this is achieved by increasing the number of measurements performed [20]. However, this can be time consuming and demanding for the patient. For IOS, only R20 measurements showed significant changes after salbutamol. This indicates that IOS is most useful for measuring changes in central airway calibre in healthy subjects. In mild asthmatics we found that increased pulmonary responsiveness to salbutamol was most effectively demonstrated by the plethysmographic measurement of airway conductance, as this was the only method that detected the effects of salbutamol 10 µg. MMEF was almost as sensitive as sGaw, while FEV1 was less sensitive than either of these measurements. FEV1 is often used as the ‘gold standard’ in clinical trials of mild asthmatics. However, our results indicate that MMEF, which can easily be obtained at the same time as FEV1 readings, should be used more frequently as it is a more sensitive measurement. Furthermore, we found that IOS reactance and resistance measurements were more sensitive than FEV1 in mild asthmatics. The potential use of IOS measurements in clinical trials of asthma should be further explored as it provides a simple, sensitive alternative to the measurement of FEV1.
In moderate asthmatics there was no difference in the sensitivity of the methods, as spirometry, plethysmography and IOS were all able to demonstrate significant physiological effects after salbutamol 10 µg. These results contrast with mild asthmatics, where sGaw was the most sensitive method. This indicates that the sensitivity of pulmonary function measurements to detect bronchodilatation varies with the severity of airflow obstruction.
Our study has primarily evaluated the sensitivity of pulmonary function test methods to detect small changes at the lower end of the dose–response curve for salbutamol. However, the differences in the shapes of the curves are also of interest, e.g. in moderate asthmatics the plateau of the dose–response appears to have been reached at 800 µg for R5, but not for R20 and sGaw. Further more detailed studies are required to examine differences in pulmonary dose–response curve shapes with these lung function methods.
We also assessed the relationship between the magnitude of the change in FEV1 and other pulmonary function measurements. This relationship was dependent on both the dose of drug and the subject group studied. In particular, the results in moderate asthmatics were very different from healthy volunteers and mild asthmatics. The underlying pathophysiological reasons for these differences between mild and moderate asthmatics are unclear, and need further study.
Our findings of changes in respiratory reactance after bronchodilatation in asthmatics have been observed in other studies [21, 22]. It has been suggested that this phenomenon is due to an improvement in peripheral airway obstruction which decreases shunting into less compliant central airways and improves transfer of air into the lung peripheries [23]. There may also be improved linkage and interaction of the airways with the lung tissue as a result of altered smooth muscle tone [24]. Regardless of the possible underlying mechanism, the results of the current and previous studies [21, 22] support the use of Xrs measurements for assessing the effects of drugs on lung compliance in asthmatics.
The practicalities of a technique are important when deciding on the most appropriate measurement for use in clinical trials. While spirometry is easy to perform, it is also effort dependent, and can lead to a temporary alteration in bronchomotor tone due to the deep inspiration required [11, 25]. Plethysmography is a more complex procedure that some subjects find difficult to perform as it involves ‘panting’. In contrast, IOS requires tidal breathing and so does not alter bronchomotor tone and is easy for subjects to perform. The effects of deep inspiration on bronchomotor tone need to be considered when deciding on the order of pulmonary function tests; we performed spirometry after IOS and plethysmography for this reason. The practical advantages of IOS, in conjunction with its ability to detect dose–response effects in asthmatics, make it an ideal technique for use in clinical trials. However, the requirements of regulatory authorities are often the main factor in determining the choice of lung function technique to be used in a clinical trial. This explains the frequent use of FEV1 in this setting. Our results demonstrate that the use of additional measurements can give supplementary information and should be encouraged.
In conclusion, we have shown that the most sensitive method for assessing bronchodilatation is different in healthy volunteers compared with asthmatics. Furthermore, the sensitivity of different pulmonary function techniques varies with the severity of airflow obstruction. These data, in conjunction with consideration of the practicalities of the methods, should be used to determine the most appropriate measurements of pulmonary physiology in clinical trials.
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