Intersubject Variability in Particle Deposition Does Not Explain Variability in Responsiveness to Methacholine 1 - 3 PAULA J. ANDERSON, ERIC GARSHICK, JAMES D. BLANCHARD, HENRY A. FELDMAN, and JOSEPH D. BRAIN SUMMARY How variable is the deposition of inhaled methacholine (MCH) in the respiratory tract during a challenge test? Does this variability contribute to the variability of airway responsiveness? Toexamine these questions we estimated the deposition of polydisperse MCHdroplets by measur- ing the deposition of surrogate diethylhexyl sebacate (DEHS)droplets that were similar in size (1.5 urn) but monodlsperse. Light scattering photometry and flow measurements were used to compute Inspired and expired DEHS particle number. Deposition of DEHS during 4 breaths was measured twice at baseline and after every dose of MCHduring an abbreviated challenge test in 16subjects. Deposition was then compared with reactivity. Reactivity to MCHwas expressed as the dose-response slope; it was calculated as percent final change in FEV,/cumulative dose MCHInhaled. Dose-response slopes ranged from zero(nonreactive) to -15.0 (very reactive) %/llmol (mean - 3.2 ± 5.3 SO).Seven subjects had a 20% or greater decrement in FEV, after their highest MCH dose. Baseline DEHS deposition, which ranged from 66 to 84% (mean 77 ± 5SO),was not significantly different between responders and nonresponders and was not a significant predictor of the dose-response slope. Reactivity was significantly associated with an Increase in deposition produced by MCH(p < 0.007). This increase was small, however (relative change < 7%), so that the effect on the deposited dose of MCH was minimal. We conclude that, with the breathing pattern used, individual differences in DEHS(and MCH)deposition were small and contributed little to intersubject variability of respon- siveness to inhaled MCH. AM REV RESPIR DIS 1991; 144:649-654 Introduction Bronchial hyperreactivity has long been considered a diagnostic feature of asth- ma (1,2); recent reports also suggest that it may be a risk factor for the develop- ment or progression of lung disease (3, 4). Hyperreactivity has been document- ed in asymptomatic subjects and in those with hay fever, chronic bronchitis, and other pulmonary diseases. In order to quantify hyperreactivity, bronchoprovo- cation studies using aerosolized drugs have been utilized in both clinical settings and in epidemiologic screening of large population groups (3-6). Many variables affect the airway re- sponse to an inhaled bronchoconstrict- ing agent; one of the most important is the dose of drug administered. Yetdose should be defined as the amount of drug that is actually deposited in the lungs. It has been shown that there is consider- able variability among normal subjects in the percent deposition of inhaled aero- sols, even during carefully standardized breathing conditions (7-9). It has also been shown that in subjects with airway obstruction, particle deposition is usu- ally increased (10-13). Nevertheless, the importance of the fraction of an inhaled drug that actually deposits in the lungs (percent deposition) as a determinant of airway responsiveness has not been fully evaluated. Previous investigators have measured the mass of a bronchocon- stricting drug that is deposited in the re- spiratory tract by using a drug labeled with fluorescent (14, 15) or radioactive (16) tracers. However, to date, no depo- sition values have been obtained using particle concentration measurements at the mouth during the course of bron- choprovocation testing. How variable is the deposition of in- haled methacholine (MCH), and to what extent does this variability contribute to the variability of airway responsiveness? Moreover, does drug deposition change significantly during the course of an MCH challenge test? To examine these questions we measured percent deposi- tion of a comparably sized surrogate aerosol in 16subjects before and during an MCH challenge test performed as it might be during clinical testing or epidemiologic screening. Methods Study Cohort Sixteen subjects were recruited either from laboratory personnel (fivemen, one woman) or from patients in the alcohol rehabilitation program at 'the Brockton Division of the Brockton/West Roxbury Veterans Affairs Medical Center (two outpatient, eight inpa- tient). Informed consent was obtained from all subjects and the research protocol was reviewed and approved by the review boards for human studies at both the Harvard School of Public Health and the Brockton/West Rox- bury VA Medical Center. All subjects were free of symptomatic ischemic heart disease and had a baseline FEV1 of 60070 of predicted or greater. One subject had a history of doctor-diagnosed asthma as a child. Seven subjects had never smoked cigarettes, eight were current smokers, and one was an ex- smoker, as classified by the American Tho- racic Society DLD-78 respiratory question- naire (17). No subject was using bronchodi- lators, but one was taking propranolol. One had used an antihistamine within 7 h, and another had taken an unknown cough medi- cine. The mean age was 42 ± 8 yr (range 30 to 59 yr). Mean baseline FVC was 5.07 ± 1.04 (SD) L (range 3.37 to 7.25 L), and mean base- line FEV 1 was 3.77 ± 0.82 L (range 2.09 to 5.06 L). The mean percent predicted FVC was 106 ± 10% (range 85 to 121 %), and the mean percent predicted FEV1 was 93 ± 13 0,10 (range 69 to 112%) using the predicted values of Knudson and colleagues (18). Testing was done without regard for recent cigarette or caffeine use. Methacholine Challenge Protocol MCH challenge testing utilized the abbreviat- (Received in original form May 7, 1990 and in revised form February 7, 1991) 1 From the Respiratory Biology Program, Har- vard School of Public Health, Boston, Mas- sachusetts, the Medical Service, Brockton/West Roxbury Veterans Administration Medical Center, Brockton, Massachusetts, and the Channing Lab- oratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. 2 Supported by Specialized Center of Research Grant HL-19170and Grant HL-07118 from the Na- tional Heart, Lung, and Blood Institute and by VA Medical Research Funds. J Correspondence and requests for reprints should be addressed to Dr. Joseph D. Brain, Re- spiratory Biology Program, Harvard School of Pub- lic Health, 665 Huntington Avenue, Boston, MA 02115. 649