Drug delivery by nebulization: "reality testing".
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Aerosols↗
Biomedical subjects
G C Smaldone
Publications and source records attributed to G C Smaldone.
Deposition patterns of nebulized drugs: is the pattern important?
It is logical to assume that the efficacy of an aerosolized drug should be related to the local airway dose. To test this assumption, it is necessary to have some index of the distribution of deposited drug within the airway and a measure of efficacy. However, most studies, in which the regional distribution of a deposited radiolabeled aerosol throughout the lung has been carefully measured, have not been directly related to the efficacy of any drug. For example, the deposition pattern is critical in terms of interpreting studies of mucociliary clearance but, in those cases, the radiolabel is usually not tied to a therapeutic agonist. Most classical studies measuring the efficacy of an aerosolized drug involve bronchodilators. While bronchodilation itself has been shown to affect subsequent regional ventilation and particle deposition, targeting specific airways has never been shown to be critical for bronchodilator efficacy. This situation may be different for agents which have a more delayed effect; for example, aerosolized steroids and antibiotics. Little data are available that directly address this question. We have developed techniques for measuring total and regional lung deposition for purposes of addressing the issue of airway site versus drug efficacy. Presently, we have information on methacholine, which is useful for measurement of airway reactivity, gentamicin, pentamidine and cyclosporin. While many factors affect total and regional deposition, we have found that the underlying disease process in the lung is a major determinant of the final deposition pattern.(ABSTRACT TRUNCATED AT 250 WORDS)
Aerosols↗
Aerosol deposition in mechanically ventilated patients. Optimizing nebulizer delivery.
Previous studies have suggested that nebulizers are inefficient in delivering aerosolized medication to the lung in patients supported by mechanical ventilation. In a recent bench study, we characterized factors that may affect aerosol delivery, i.e., nebulizer type, ventilator settings (duty cycle), volume fill, and humidification as well as technical factors affecting measurement of deposition (e.g., radiolabeled compounds). Utilizing the predictions from our bench data, the present study was designed to assess nebulized aerosol delivery to ventilated patients under optimal conditions. Seven patients who were receiving mechanical ventilation (Bear II) via tracheostomy tube (TT) were studied. The humidifier was turned off. The test aerosol, a saline solution labeled with 99mTechnetium bound to human serum albumin (99mTc-HSA), was administered via a jet nebulizer (AeroTech II, 1.1 +/- 1.8 microns [mass median aerodynamic diameter, MMAD, geometric standard deviation, sigma g]), which was incorporated into the ventilator circuit and run to dryness. Inhaled and deposited radioactivity were measured by a mass balance/filter technique. TT versus lung deposition were quantified by removal of the inner cannula and direct measurement of TT deposition in a well counter. Inspiratory versus expiratory components of TT deposition were separated via bench techniques for each TT tube and breathing pattern. The regional distribution of deposited radioactivity was confirmed by gamma camera scans before and after TT removal. Measured radioactivity at each site was expressed as a percentage of nebulizer charge (i.e., the quantity of radioactivity originally placed in the nebulizer). On average, 30.6 +/- 6.3% (SD) of the charge was inhaled by the ventilated patients. Mean deposition in the TT during inspiration was 2.6 +/- 0.5%.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Lobar pentamidine levels and Pneumocystis carinii pneumonia following aerosolized pentamidine.
Recent studies have suggested that failure of pentamidine prophylaxis against Pneumocystis carinii pneumonia (PCP) may be due to reduced deposition of pentamidine in the upper lobes. In this study, we performed bronchoalveolar lavage from the apical segment of the upper lobe and the middle lobe in 51 HIV-positive patients, all of whom were receiving prophylaxis with aerosolized pentamidine, who had presented with acute respiratory symptoms. Lavage fluid from each lobe was assayed for pentamidine using high-performance liquid chromatography (HPLC). The number of clusters of P carinii were counted after staining with a Wright-Giemsa stain. The patients were subclassified as PCP-positive (32 patients) and PCP-negative (19 patients) on the basis of the presence/absence of P carinii clusters in their BAL fluid. The concentration of pentamidine in the upper lobe compared with the middle lobe was no different (using paired Student's t tests) for either PCP-positive patients or PCP-negative patients. In comparing the positive with the negative subjects, using unpaired Student's t test, there was no difference in the concentration of pentamidine in the upper lobe or the middle lobe. For PCP-positive patients, the numbers of P carinii clusters were on average higher in the upper lobes (mean +/- SD: upper = 14.9 +/- 16.6, middle 7.5 +/- 10.8, p = 0.013, paired Student's t test), but there was no correlation between lobar P carinii cluster counts and pentamidine levels. We conclude that the absence of a relationship between cluster count and pentamidine level, the similarity in regional pentamidine levels between upper and middle lobes, as well as the similarity in pentamidine levels between the PCP-positive and PCP-negative groups indicate that the regional dose of pentamidine is not the determining factor as to whether aerosolized pentamidine prophylaxis will succeed or fail.
Adult↗
Regional deposition and regional ventilation during inhalation of pentamidine.
In most patients, the deposition of aerosolized pentamidine (AP) is less in the apex of the lung relative to the base. As the apex of the lung is relatively less ventilated than the base, it is possible that reduced regional ventilation may explain the inhomogeneity in regional drug deposition. The purpose of this study was to measure the relationship between regional deposition of AP and regional ventilation, and the influence of particle size and airway caliber on this relationship. Ten subjects with HIV infection who were receiving prophylaxis with AP were recruited. Using krypton (81mKr), we measured regional ventilation during treatment with AP, labeled with 99mTc. Two nebulizers were used (Respirgard II and Fisoneb) that produced particles of different size. In addition, patients were studied with and without a bronchodilator because changes in airway geometry can affect sites of particle deposition. There was no significant correlation between regional ventilation and regional particle deposition (r = 0.00, linear regression). Particle deposition in the upper lobes relative to the lower lobes was less than would be predicted by regional ventilation, by a ratio of 0.84 +/- 0.03 (mean +/- SE). Using two-way analysis of variance (ANOVA), the upper to lower zone deposition pattern was not affected by either nebulizer or by the use of albuterol. The Fisoneb had significantly more central deposition relative to the jet nebulizer (mean +/- SE, skC/P: Fisoneb 1.3 +/- 0.1, Respirgard 1.1 +/- 0.1, p = 0.005, two-way ANOVA). The use of a bronchodilator did not significantly affect the central/peripheral deposition pattern. We conclude that differences in deposition between upper and lower lung regions are not accounted for simply by differences in regional ventilation in patients undergoing prophylaxis with AP. In assessing the cause of regional inhomogeneities of pharmaceutical aerosol deposition (and in devising strategies to achieve more uniform distribution), regional ventilation should be measured directly rather than be inferred from the deposition pattern of the aerosol.
Administration, Inhalation↗
Changing patterns of aerosol deposition during methacholine bronchoprovocation.
During bronchoprovocation testing with methacholine, induced changes in airway geometry are known to affect sites of drug deposition. However, it is not known if changes in these sites determine measured responsiveness. We assessed the importance of sites of deposition as determinants of reactivity by comparing particle behavior in two subject groups with and without hyperresponsiveness. By administering radiolabeled aerosols of similar aerodynamic characteristics to methacholine aerosol, we measured the deposition pattern in terms of the specific central to peripheral ratio (sC/P) before and after methacholine inhalation (sC/P1 and sC/P2, respectively) and thereby quantified the changes in deposition sites that occur during the course of a typical bronchoprovocation test. Subjects whose FEV1 decreased by 20 percent or greater were classified as methacholine responsive (MR; nine subjects), and the remainder were classified as non-methacholine responsive (NMR; seven subjects). The two groups had similar baseline FEV1 percent predicted (FEV1 percent) and initial deposition patterns (sC/P1) with particles depositing primarily in peripheral airways (mean +/- SE; sC/P1 1.43 +/- 0.070 and 1.39 +/- 0.65, MR and NMR, respectively, p = NS). Following methacholine inhalation, the deposition pattern changes markedly for all subjects with particles depositing primarily in central airways (sC/P2 2.58 +/- 0.24, p = 0.001, and 2.15 +/- 0.22, p = 0.001 from baseline, p = NS between groups) By definition, the MR subjects had a significantly greater change in FEV1 than the NMR subjects. Preferential deposition in central airways occurs in all subjects during bronchoprovocation testing and does not significantly determine methacholine responsiveness.
Administration, Inhalation↗
Regional impairment of mucociliary clearance in chronic obstructive pulmonary disease.
Asthmatic subjects with tidal expiratory flow limitation have mucociliary clearance (MC) impairment in central airways. Because tidal flow limitation develops in COPD, it is possible that regional MC in these patients also may be affected. We tested this hypothesis by measuring MC in the presence or absence of flow limitations. Patients with COPD and chronic flow limitation were compared with non-flow-limited normal volunteers. Deposition was normalized for regional lung volume and expressed as the specific central to peripheral (sC/P) ratio. In COPD subjects, clearance from the whole lung and central airways was significantly different from that of normal subjects after 20 min of observation. In the peripheral airways, there were no significant differences between COPD and normal subjects. An alternative analysis of regional MC indicated patients retained particles in central airways while normal subjects, with intact MC, emptied central airways. Thus, COPD subjects with tidal expiratory flow limitation have impaired MC in their central airways.
Adolescent↗
Nebulizer function during mechanical ventilation.
In the setting of mechanical ventilation, recent studies have cast doubt on the ability of nebulizer systems to deliver adequate amounts of medication. We therefore studied ventilator-related and nebulizer-related factors that could potentially affect the amount of aerosol inhaled by an intubated subject. Utilizing two separate protocols, we used a bench model of a ventilator circuit, radiolabeled (technetium pertechnetate, 99mTc) saline droplets and a filter technique to measure the percentage of radioaerosol delivered. First, we compared four commercially available jet nebulizers and found that there were significant differences in rate of aerosol production between systems, ranging from 3 to 37%. Delivered aerosol was measured at different ventilator settings, and it was found that the duty cycle can potentially influence output by sevenfold. Some nebulizers were also sensitive to changes in the initial volume of solution placed in the nebulizer. The inclusion of a humidification device significantly reduced output by a mean of 41 +/- 3.5%, but it did not affect particle distribution. Endotracheal tube diameter was not an important variable. Then, with the effects of the above variables established, a separate series of experiments was performed to test whether the use of different radiolabeling compounds can confound the measurement of inhaled drugs. Two nebulizers (AeroTech II and Twin Jet) and pentamidine as the test drug were studied with fixed ventilator settings, treatment time, endotracheal tube size, and volume fill. No humidification was used. The nebulizer solution was labeled with 99mTc, which was bound to either human serum albumin (HSA) or sulfur colloid (SC).(ABSTRACT TRUNCATED AT 250 WORDS)
Aerosols↗
Mucociliary clearance in adult asthma.
Severe impairment of mucociliary clearance (MC) in hospitalized asthmatics has recently been demonstrated in peripheral and central airways. MC was also shown to improve with clinical recovery and hospital discharge (2). In the present study, we measure MC in chronic, stable asthma in subjects with a wide range of obstruction to see if MC was related to the severity of chronic disease. We separated the subjects into those with severe obstruction with expiratory flow limitation during tidal breathing (FL subjects) and those without tidal flow limitation (NFL subjects) to see if the presence of chronic flow limitation was associated with regional MC abnormalities. Seventeen asthmatic patients were studied. Mucociliary clearance was assessed using inhaled radioaerosol and serial measurements of the retention of radioactivity over 2 h. By controlling breathing pattern, the initial pattern of deposition in the lungs was matched, with all subjects having a predominance of particles in the central airways. This pattern was normalized for regional lung volume using a xenon equilibrium scan and expressed as a specific central to peripheral (sC/P) ratio. The percentage retention of deposited radioactivity at 120 min ranged from 19 to 83% (mean, 52%). FL subjects had a mean retention at 120 min of 66% (range, 55 to 83%). The NFL subjects had a mean retention at 120 min of 33% (range, 19 to 51%). Throughout the 2-h study period, retention by the FL group was significantly greater than that of the NFL group with separation of 95% confidence intervals.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Deposition of aerosolized pentamidine and failure of pneumocystis prophylaxis.
OBJECTIVE: To determine if outcome of Pneumocystis carinii prophylaxis is related to total lung dose of aerosolized pentamidine. SETTING: AIDS treatment centers at a VA and University Hospital. PATIENTS: Fifty-eight HIV-infected patients receiving P carinii prophylaxis with aerosolized pentamidine using a nebulizer (CIS-US AeroTech II) were followed up over a 90-week period. Treatment consisted of 60 to 90 mg every two weeks. MEASUREMENTS: In all patients, deposition of pentamidine aerosol was measured using a radioaerosol filter technique. Factors thought to be important in deposition, nebulizer output and breathing pattern were also measured. Six months later, repeated deposition studies were performed in 20 patients. Pentamidine dose to the lung was related to occurrence of P carinii pneumonia and correlated with nebulizer function and breathing parameters. Outcome was assessed in terms of pentamidine deposition and patient characteristics, including demographic, immunologic, physiologic, and medical variables. RESULTS: Ten patients (17.2 percent) had development of P carinii pneumonia. However, pentamidine deposited in the failures (8.18 +/- 4.74 mg) was no different than deposition in protected patients (6.39 +/- 3.07 mg, p = NS). Most of the variability in deposition was accounted for by variability in nebulizer output (r = 0.919, p less than 0.001). Deposition did not significantly correlate with any of the measured breathing parameters. Serial deposition measurements were not significantly different by paired analysis. The incidence of P carinii pneumonia did not correlate with any measured patient characteristic. CONCLUSIONS: Failure of aerosolized pentamidine prophylaxis is not related to total lung dose of pentamidine. Other factors such as inadequate microscopic deposition between alveoli, pentamidine clearance, or drug resistance may be important. In HIV-infected patients, interpatient variability in aerosol deposition can be reduced by reducing variability in nebulizer output rather than control of breathing pattern.
Aerosols↗
Exposure of health care workers to aerosolized pentamidine.
In patients, urinary levels of pentamidine have been shown to reflect pulmonary deposition of aerosolized drug. Using urinary levels and air filter samples, we assessed factors responsible for health care worker (HCW) exposure. We measured serial urine samples in HCWs who administered aerosol pentamidine over an 11-month period and compared them with serial urine levels measured over 30 days in a normal volunteer in whose lungs a known amount of pentamidine (3.39 mg) had been deposited. Ambient exposure to pentamidine was determined by continuous high volume air sampling in the treatment room during routine therapy. In addition, the amount of pentamidine released by six HIV-positive subjects, performing tidal breathing with a Respirgard II nebulizer in an airtight booth, was measured by extracting air from the booth through a filter. The effect of adding noseclips, of coughing (with nebulizer shut down), and of removing the nebulizer from the patient's mouth without turning it off, were determined. Pentamidine in the urine of the normal volunteer reached a peak concentration of 9.5 ng/mg creatinine/ml and was detectable for 30 days following the exposure. In HCWs, pentamidine was detected intermittently in four of five individuals with levels as high as 18.2 ng/mg creatinine/ml. Samples of ambient treatment room air indicated small daily releases of pentamidine (0.013 +/- 0.02 mg per patient treated), but simultaneous urine levels in HCWs were negative. The data from the airtight booth revealed that removing the nebulizer from a patient's mouth without turning it off caused a 360-fold increased in pentamidine release compared to tidal breathing. Coughing resulted in a 6.9 (range 0.9-14.2)-fold increase in release, while the addition of noseclips had no significant effect. The pattern of intermittently positive urine tests and the low levels of ambient pentamidine detected in the air of the treatment room suggest that HCWs are being exposed to episodic but high concentrations of pentamidine. High level exposure is most likely to occur during treatment interruptions which are usually precipitated by coughing episodes. Because of the intermittent pattern of exposure and slow clearance of pentamidine, urine assay is useful for detecting high intermittent exposure. Random air sampling is a sensitive indicator of low level exposures but may not detect episodic high level releases.
Aerosols↗
Detection of inhaled pentamidine in health care workers.
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Aerosols↗
Technetium 99m radiolabeling of aerosolized drug particles from metered dose inhalers.
To assess mechanisms of bronchodilation and effectiveness of metered dose inhalers, it may be useful to determine sites of drug deposition in the lung. To establish suitable test aerosols, two brands of metered dose inhalers containing bronchodilator (Brethaire, Proventil) were radiolabeled with technetium ( 99mTc) and tested to determine if the distribution of radioisotope in the aerosol was representative of the distribution of agonist activity. Cascade impaction was used to determine the particle size distribution of the radioisotope and drug aerosols by assaying each state of the cascade using scintillation and HPLC techniques. Possible influences of the radiolabeling method and delivery techniques on the particle distribution were assessed by analyzing distributions from nonradiolabeled inhalers using HPLC. For these drugs, there was an excellent correlation between the distribution of radioactivity and the drug within the captured aerosol (Brethaire r = 0.994, Proventil r = 0.998, 20 - 200 consecutive puffs). Distributions were close to log-normal and differences in mass median aerodynamic diameter (MMAD) between the radioisotope and agonist activities were not significant (Brethaire, MMAD +/- sigma g, radiolabel vs drug = 4.7 +/- 2.1 mum, vs 4.4 +/- 1.7 mum, and Proventil, 2.5 +/- 2.1 mum, vs 2.4 +/- 2.0 mum. Non-labeled inhalers produced similar drug distributions (Brethaire, 4.2 +/- 1.8 mum, and Proventil 2.0 +/- 1.9 mum). Pausing between actuations resulted in slightly smaller distributions (Brethaire, 3.6 +/- 1.8 mum, Proventil 1.8 +/- 1.8 mum, 20 puffs-60 sec pauses) but the differences were not significant. In addition, to search for multimodal distributions and assess the accuracy of the MMAD measurement via our cascade impactor (Delron), we also measured the distribution of the mass of material within the aerosols using a weight-sensitive cascade (California Measurements). Using the latter device (1 puff), the mass distributions of both aerosols were similar to the values obtained from the puffs with pauses (Brethaire 3.8 +/- 2.3 mum, Proventil 1.4 +/- 2.2 mum). Multi-modal distributions were not found. By all assessments, the distributions were nearly log-normal with drug activity well described by the radiolabel.
Bronchodilator Agents↗
Drug delivery via aerosol systems: concept of "aerosol inhaled".
The mass of aerosol inhaled is primarily a function of the patient's breathing pattern and the aerosol delivery system. Once inhaled, deposition is governed by factors related to the properties of the aerosol and the individual characteristics of the patient (e.g., particle size distribution, airway geometry, and residence time). This paper will center upon the actual generation and delivery of clinical aerosols by jet nebulizers and assess variability in aerosol delivery. Because of the practical difficulties in predicting nebulizer function from first principles, it will be advocated that nebulizer function be directly measured for each clinical situation. Terms like "nebulizer output", "efficiency", etc. are to be avoided. The following definition is proposed: "aerosol inhaled" represents that quantity of drug actually delivered by a given nebulizer for a defined breathing pattern and period of time. The concept of "aerosol inhaled" allows a direct comparison of the quantity of drug delivered by different nebulizer systems and adjustment of dose of a given therapeutic agent. Bench testing of aerosol systems and measurement of "aerosol inhaled" can be made in the laboratory if careful attention is paid to the relationship between laboratory conditions and actual use, including the particle distribution and the accuracy of a radiolabel in estimating the quantity of drug nebulized.
Administration, Inhalation↗
Factors determining pulmonary deposition of aerosolized pentamidine in patients with human immunodeficiency virus infection.
Although aerosolized pentamidine (AP) has recently been approved for prophylaxis and is undergoing clinical trials for treatment of pneumocystis, pneumonia (PCP), factors important in the deposition of AP have not been described. Using radioaerosol techniques, deposition was measured in 22 patients receiving AP for prophylaxis or treatment of PCP. In all patients total and regional deposition of pentamidine, breathing pattern, pulmonary function (PFT), regional ventilation, and type of nebulizer were analyzed. Bronchoalveolar lavage (BAL) was performed 24 h after inhalation to assess the relationship between pentamidine levels in BAL fluid and measured aerosol deposition. The nebulizers tested were the Marquest Respirgard II and the Cadema AeroTech II, both previously characterized in our laboratory. The aerosol particles consist of water droplets containing dissolved pentamidine and technetium 99m bound to albumin. Analysis of particles sampled during inhalation via cascade impaction confirmed a close relationship between radioactivity in the droplets and the concentration of pentamidine as measured by HPLC (r = 0.971, p less than 0.0001; n = 18). Deposition was measured by capturing inhaled and exhaled particles on absolute filters and measuring radioactivity. This technique allows the determination of the deposition fraction (DF, the fraction of the amount inhaled that is deposited), which provides information on factors strictly related to the patient. To confirm the filter measurements, pentamidine deposition was also measured by gamma camera. The camera measurement was possible because each patient's thoracic attenuation of radioactivity was determined by a quantitative perfusion scan (mg pentamidine deposited via both techniques, r = 0.949, p less than 0.0001; n = 26). Regional lung volume and ventilation were determined by xenon 133 equilibrium scan and washout. Pentamidine deposition varied markedly between patients, but BAL levels of pentamidine significantly correlated with measured deposition (r = 0.819, p less than 0.01; n = 9). DF averaged 0.621 +/- 0.027 (SEM) and did not correlate with any measured lung parameter, including breathing pattern and PFT. Regional deposition did not correlate with regional ventilation. The major factor influencing pentamidine deposition was aerosol delivery (mg deposited versus mg inhaled; r = 0.963, p less than 0.0001; n = 26). The nebulizer was an important determinant of aerosol delivery, with the AeroTech delivering between 2.5 and 5 times more drug than the Respirgard. These observations are important in assessing treatment failure and cost of therapy.
Aerosols↗
Changes in mucociliary clearance during acute exacerbations of asthma.
Previous studies have suggested that mucociliary clearance (MC) is impaired in asthmatic subjects. If so, impaired clearance may be an important factor in acute exacerbation. We proposed that if MC plays a significant role in acute illness, MC should be impaired during the exacerbation but improve after recovery. To test this hypothesis, five asthmatic patients with attacks requiring hospitalization underwent measurement of MC using radiolabeled aerosol and a gamma camera. They were studied on the second or third day after admission with repeat measurements after discharge. Spirometry was performed before all studies. After an equilibrium xenon scan (133Xe), which defined lung borders and measured regional volume, radiolabeled saline particles containing technetium-labeled (99mTC) sulfur colloid were deposited and used to label airway mucus. Deposition patterns were matched by regulating particle distribution and breathing pattern. MC was then measured as percentage retention of radioactivity at 10-min intervals for 2 h. When hospitalized, 96.0 +/- 2.06% (SEM) of the initial radioactivity was retained in the lung after 2 h, indicating little clearance of mucus from the lung. In fact, no significant changes were detected when activity at 120 min was compared with measurements at 10 min (99.2 +/- 0.22%, NS). After discharge clearance was markedly enhanced. That is, retention of lung activity was significantly lower at all time intervals from 10 min onward, with only 70.9 +/- 3.86% retained at 120 min (p = 0.008). During an asthmatic attack warranting hospital admission, MC is significantly impaired, with marked improvement following recovery.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
Urine pentamidine as an indicator of lung pentamidine in patients receiving aerosol therapy.
To determine if urine pentamidine was reflective of lung pentamidine, we compared levels of the drug in bronchoalveolar lavage fluid and simultaneously obtained urine. Thirty-one patients who were receiving aerosolized pentamidine either as treatment or as prophylaxis underwent BAL and submitted urine samples for pentamidine analysis. Pentamidine was analyzed in both phases of BAL fluid (supernatant and cell pellet) and in urine using high performance liquid chromatography. Urine results were normalized for creatinine. Patients were categorized as prophylaxis failures (active Pneumocystis carinii pneumonia on prophylaxis), electives (free from PCP on prophylaxis), treatment (daily AP in treatment doses for active PCP, or miscellaneous (single dose of AP). Levels in BAL fluid and urine varied widely over several orders of magnitude. However, for all patients, we found a highly significant relationship between BAL supernatant and urine (r = 0.97, p less than 0.0001). No statistical differences were found when comparing levels of pentamidine between failures and electives; however, the number of failures was small. We conclude that urine pentamidine is related to lung pentamidine and can be used as a clinical indicator in patients receiving aerosolized therapy.
Administration, Inhalation↗
Use of aerosols to estimate mean air-space size in chronic obstructive pulmonary disease.
Using in vivo measures of aerosol recovery (RC) as a function of breath-hold time (t) (Gebhart et al. J. Appl. Physiol. 51: 465-476, 1981), we estimated the mean diameter (D) of the pulmonary air spaces in subjects diagnosed with chronic obstructive pulmonary disease (COPD) (n = 8) and in subjects with normal pulmonary function (n = 10). For each subject, RC (aerosol expired/aerosol inspired) decreased exponentially with t. Based on a model of the lung as a system of randomly oriented cylindrical tubes, the half time (t1/2) (i.e., the breath-hold time to reach 50% of RC with no breath hold) is proportional to a mean diameter (D) of air spaces filled with aerosol. Subjects with normal pulmonary function had a mean t1/2 = 6.5 +/- 0.8 s, corresponding to a mean D = 0.36 +/- 0.05 mm. On the other hand, subjects with COPD had a mean t1/2 = 12.7 +/- 3.2 s, corresponding to a mean D = 0.70 +/- 0.18 mm [i.e., twice as large (P less than 0.01) as normal subjects]. Furthermore, D correlated significantly with diffusing capacity in the patients with COPD (r = -0.95, P less than 0.001 for D vs. percent predicted diffusing capacity of CO) but not with any other measure of pulmonary function. In contrast, D varied only slightly in normals and did not correlate with any measure of pulmonary function. We conclude that in vivo measures of RC vs. t, in conjunction with other pulmonary function tests, may be a useful tool for identifying actual changes in pulmonary air-space sizes associated with pulmonary disease.
Aerosols↗