Experience using centralized spirometry in the phase 2 randomized, placebo-controlled, double-blind trial of denufosol in patients with mild to moderate cystic fibrosis.

BACKGROUND: Centralized spirometry may significantly improve quality of spirometry and reduce variability of this outcome measure in clinical trials in cystic fibrosis (CF). METHODS: Spirometry was performed during the phase 2 randomized, placebo-controlled, double-blind clinical trial of denufosol in patients with mild to moderate CF using American Thoracic Society guidelines. Uniform spirometers were used with electronic data transmission of all the data to a reading center. Spirometry was evaluated for quality by a central reader based on start of test, cough during the test, and evidence of a plateau. RESULTS: A total of 1418 spirometry values were assessed in 89 subjects during the trial. In only 5 instances did the central reading center need to give feedback to sites regarding the quality of spirometry. The study site data matched the central reading center's data for all but 78 (6%) spirometry values in 33 patients. Many of these differences were small with only 35 (3%) values differing by more than 50 mL in 26 patients. CONCLUSION: Spirometry in this clinical trial was of high quality with low rate of significant centralized over-read.

Airway responses to a diluent used in the methacholine challenge test.

BACKGROUND: Inhalation of diluent is often used in performing methacholine challenge tests, but its elimination has been suggested because marked falls in FEV1 after diluent inhalation have not been documented and performing this step is time-consuming. OBJECTIVE: We investigated the frequency and magnitude of response to the inhalation of diluent, and if there were any systematic effects in determining the PC20 using the baseline and postdiluent spirometric measurements. METHODS: All methacholine challenges performed during a 6-year period (N = 3,902) were reviewed retrospectively. RESULTS: The maximum increase and decrease in FEV1 and FVC from baseline were 56.3% and -41.4%, respectively, and 61.7% and -40.3%, respectively. The mean absolute changes from baseline in FEV1 and FVC were -0.018 L and -0.026 L, respectively. There was a highly significant correlation (r2 = 0.96; P < .0001) between the PC20 baseline and PC20 postdiluent values, and a mean difference of 0.041 mg/mL (P < .0001), with the PC20 postdiluent being higher. CONCLUSIONS: These data do not provide strong evidence to support either using or eliminating the diluent stage. It is clear that there are frequent and sometimes large changes in FVC and FEV1 after the inhalation of diluent containing phenol and sodium bicarbonate buffer. If a laboratory intends to report changes in airway function qualitatively (ie, positive or negative), the diluent stage may not be necessary. However, if a laboratory intends to report bronchial challenge data from inhaling methacholine in a quantitative fashion and report a continuous variable such as PC20, a diluent stage is recommended.

Single-breath carbon monoxide diffusing capacity.

Measurement of DL(CO) remains a clinically useful way to assess transfer of gases across the lung. It is important, however, to be vigilant in controlling the sources of variation and to be aware of those that remain when interpreting the measured values.

Correlation of cat-hair (Fel d1) prick skin test to airway response using a live-cat-room challenge model.

The purpose of this study was to document the relationship between prick skin test, airway, and common allergy symptom responses to natural cat exposure. Twenty-nine volunteers with a history of cat-hair allergy and asthma were recruited. Subjects had spirometry and prick skin test with Fel d1 on Visit 1. On Visit 2, subjects had a live-cat-room challenge with airway responses and allergy symptoms monitored. All 29 subjects had a positive skin test (wheal > or = 4 mm), but only 12 (41%) had a positive airway response (fall in FEV1 > or = 15%). There was no significant correlation between the fall in FEV1 and wheal size. All symptom scores increased significantly from baseline, but the change was not significantly related to wheal size. In summary, prick skin test response is not a good predictor of airway response or changes in allergy symptoms using the live-cat-room challenge model.

Methacholine challenge testing: safety of low starting FEV1. Asthma Clinical Research Network (ACRN).

STUDY OBJECTIVE: The lower limit for the baseline value to initiate methacholine bronchial hyperresponsiveness testing has not been well established. Recommendations have varied from > 1 L to above 80% of predicted. The objective was to determine if an FEV1 < 60% predicted was acceptable. DESIGN: Retrospective analysis of challenges in 88 patients with a baseline FEV1 of < 60% predicted (mean=45.8%; range, 22 to 59%. SETTING: Academic institutions. RESULTS: There were only four individuals whose FEV1 did not return to > 90% of baseline following one poststudy beta2-agonist treatment. All four responded to a second treatment. There were no adverse sequelae following challenge in any individual. Neither age (up to 79 years) nor gender influenced outcome. CONCLUSIONS: In chronic moderate to severe asthma, it appears that bronchial hyperresponsiveness testing can be safely performed even in those patients with a low baseline FEV1.

The effect of inspiratory maneuvers on expiratory flow rates in health and asthma: influence of lung elastic recoil.

We studied the effect of breath holding and inspiratory speed on airflow during the FVC maneuver in seven healthy subjects and eight patients with asthma. The purpose of the study was to determine whether the effects of inspiratory speed and breath holding on expiratory flow were greater in patients with asthma than in healthy individuals; whether these effects were lessened by inhalation of aerosolized bronchodilator in the patients with asthma; and whether were was a relationship between the lung elastic recoil pressure and the expiratory flow achieved during four different maneuvers. We found that peak expiratory flow rate (PEFR) was significantly lower after both a slow inspiration and a breath hold than after a fast inspiration without a breath hold. In addition, a breath hold was associated with a significantly lower FEV1. The effects of inspiratory speed and breath holding in the patients with asthma were not significantly different from those observed in the healthy subjects. There was a significant relationship between lung elastic recoil pressure at the point of onset of the FVC maneuvers (Pel Blow) and expiratory flow in both healthy and asthmatic subjects. Also, the decrease in Pel Blow with equivalent breath-hold time was greater in asthmatic subjects, which is consistent with an increase in viscoelastic elements in the lung. These findings corroborate previous suggestions that inspiratory speed and the duration of breath holding have significant implications in the performance of spirometry and peak flow measurements, and indicate the importance of standardization of the preceding inspiration when determining FEV1 and PEFR.

Attenuation of the metabisulfite-induced bronchoconstrictive response by pretreatment with cromolyn.

In a retrospective analysis of 1,544 patients who underwent provocative challenge with metabisulfite at the National Jewish Center between 1983 and 1987, an abnormal airway response to metabisulfite was found in 52 patients, an incidence of 3.4 percent. There was no relationship between this abnormal airway responsiveness to metabisulfite and the degree of airway obstruction present, or the degree of airway reactivity as assessed by the response to inhaled bronchodilator or exercise testing. In a pilot study, we found that the administration of cromolyn sodium prior to metabisulfite challenge markedly attenuated the abnormal bronchoconstrictive response in nine of ten patients. We conclude that a metabisulfite-induced bronchoconstrictive response cannot be predicted on the basis of the degree of airway obstruction or airway reactivity and that pretreatment with cromolyn sodium may attenuate the abnormal response.