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HATIPO
LU,  |
ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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We tested the hypothesis that the decrease in dyspnea in patients with COPD with inhaled albuterol
is in part due to increased diaphragmatic contractility. Eleven patients with COPD inhaled albuterol
or placebo in a double-blind randomized manner. Subsequently, dyspnea was measured while patients breathed through inspiratory resistors, and diaphragmatic contractility was quantified during maximal inspiratory efforts and after twitch stimulation of the phrenic nerves. Albuterol produced a
decrease in dyspnea (5 ± 2 to 4 ± 2 [SD] Borg units, p < 0.01), and increases in maximal transdiaphragmatic pressure (92.4 ± 37.2 to 102.8 ± 37.2 cm H2O, p < 0.03) and potentiated twitch transdiaphragmatic pressures (21.6 ± 7.1 to 25.2 ± 7.6 cm H2O, p < 0.02). The decrease in dyspnea correlated with the increases in maximal and twitch transdiaphragmatic pressures: r = 
0.64 (p = 0.04)
and r = 0.65 (p = 0.04), respectively. Compared with placebo, albuterol produced an increase in
inspiratory capacity (1.87 ± 0.71 to 2.26 ± 0.74 L, p = 0.002), which accounted for the increases in
maximal and twitch transdiaphragmatic pressures. The decrease in dyspnea correlated with the increase in inspiratory capacity (r = 0.62, p = 0.04), but not with the increase in FEV1 (r = 0.13, p = 0.72). In conclusion, albuterol relieves dyspnea and enhances respiratory muscle output in patients
with COPD primarily by improving the length-tension relationship of the diaphragm rather than by
improving its contractility.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Dyspnea, a major symptom in patients with chronic obstructive pulmonary disease (COPD), stems largely from a decrease in the capacity of inspiratory muscles to meet an increased inspiratory work load (1). In patients with COPD,
dyspnea is commonly alleviated by inhalation of 
2-adrenergic
agents such as albuterol, but the relief of dyspnea can occur
without a significant change in the degree of airway obstruction (2). The latter observation suggests that indices of airway
obstruction may poorly reflect the change in respiratory muscle load or that 2-adrenergic agents may decrease dyspnea by
enhancing the capacity of respiratory muscles to generate pressure. The second possibility is supported by the demonstration that 2-adrenergic agents improve contractility of the
isolated rat diaphragm in a dose-dependent fashion (3); interestingly, this inotropic action is magnified by foreshortening of
the diaphragm (3), a condition commonly encountered in patients with COPD. Accordingly, we tested the hypothesis that
the mechanism whereby 2-adrenergic bronchodilators alleviate dyspnea in patients with COPD is due in part to improvement in diaphragmatic contractility.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Patients
Eleven men with clinically stable COPD were studied (Table 1). Diagnosis of COPD was made according to the criteria defined by the American Thoracic Society (4). No patient with an acute exacerbation of his disease within the preceding 6 wk was enrolled. Patients were not using medications with cholinergic or sympathomimetic, either agonist or antagonist, actions, with the exception of ipratropium bromide inhaler. The study was approved by the Human Studies Subcommittee of Edward Hines Jr. Veterans Administration Hospital, and informed consent was obtained from all patients.
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Evaluation of Pulmonary Function and Dyspnea
Esophageal and gastric pressures were separately measured with two thin-walled latex balloon-tipped catheters (Erich Jaeger, Würzberg, Germany) coupled to pressure transducers (MP-45; Validyne, Northridge, CA) (5). Transdiaphragmatic pressure was obtained by electronic subtraction of the esophageal pressure from gastric pressure. Airway pressure was measured at the side tap of a flanged mouthpiece connected to a pressure transducer (MP-45; Validyne).
Flow was measured with a heated and calibrated Fleisch pneumotachograph (Hans Rudolph, Kansas, MO) connected to a differential pressure transducer (Validyne Corp.). Volumes were obtained by electronic integration of the flow signal. Inspiratory capacity was obtained by measuring the inhaled volume after asking the patients to take a further maximal effort on top of a maximal inspiration (6).
Dynamic lung compliance was calculated as the ratio of change in tidal volume between instants of zero flow over the change in transpulmonary pressure within the same breath, and the average value during 1 min of recording of resting breathing was calculated. Intrinsic positive end-expiratory pressure was measured during spontaneous breathing as the negative deflection in esophageal pressure between the onset of inspiratory effort (end-expiratory esophageal pressure) and the onset of inspiratory flow (7). To correct for the contribution of expiratory muscle activity to intrinsic positive end-expiratory pressure, the rise in gastric pressure from the end-inspiratory value to the end-expiratory value was subtracted from the initial deflection in esophageal pressure (8, 9). Lung volumes were measured by body plethysmography and timed spirometry (P.K. Morgan Ltd., Kent, UK).
The intensity of dyspnea, defined as the unpleasant sensation of labored or difficult breathing, was quantified using a modified Borg scale at the end of the resistive breathing challenges (10). Patients were asked to respectively score their sensation of air hunger and effort by answering the following questions: "How much air hunger do you feel?" and "How much effort does your breathing require?" These questions were selected a priori, based on the observation of Simon and colleagues (11) that patients with COPD most commonly select effort and air hunger to describe the unpleasant sensations of breathing that they experience.
Evaluation of Respiratory Muscle Function
Diaphragmatic compound action potentials were recorded bilaterally with surface electrodes placed at the level of the seventh and eighth intercostal space in the anterior axillary line (12). The signals were amplified, band-passed-filtered (band width 10 to 1,000 Hz; Gould Inc., Valley View, OH) and displayed on a storage oscilloscope (Gould Inc., Ilford, UK). Bilateral phrenic nerve stimulation was performed using magnetic stimulators (Magstim 200; Jali, Newton, MA) with two sets of double 40-mm coils (D40-1183.00). The area of optimal stimulation was located by moving the stimulating probe around the posterior border of the sternomastoid muscle (13). The area where stimulations elicited the compound action potential of greatest amplitude while the patient rested at end-expiratory lung volume was marked, and subsequent stimulations were performed at this site. Respiratory inductive plethysmography (NonInvasive Monitoring Systems, Miami Beach, FL) was used to ensure the proper identification of end-expiratory lung volume. All patients were studied in the seated position with the abdomen unbound.
The contribution of the diaphragm to tidal breathing was assessed by calculating the ratio of tidal change in gastric pressure over tidal change in transdiaphragmatic pressure (14). Changes in pressures were measured as the maximal deflection during a tidal inspiration compared with the gastric and transdiaphragmatic pressures at the onset of inspiratory effort.
Maximal transdiaphragmatic pressure was recorded while the patients performed a Müller maneuver of > 1-s duration against an occluded airway at end-expiratory lung volume (15). Oscilloscope recordings of transdiaphragmatic pressure were displayed to the patient as a visual feedback during Müller maneuvers.
Study Protocol
Patients were studied over three visits and were asked to refrain from
use of 2-agonists for 12 h and theophylline for 24 h before each visit.
In an attempt to distinguish between the effects of 2-agonists on respiratory muscle contractility versus lung mechanics, and thus lung volume, the patients inhaled four puffs (first six patients) or eight puffs
(last five patients) of ipratropium bromide by metered-dose inhaler 1 h
before commencement of data collection on each of the three visits.
The purpose of the first visit was to measure lung volumes and spirometry before and after albuterol and to familiarize the patient with the use of the Borg scale and the various respiratory maneuvers performed during subsequent experiments. The patient first breathed through a mouthpiece for 5 min, and then through three different linear resistors (5, 15, and 30 cm H2O/L/s; Hans Rudolph) placed in the inspiratory limb of the breathing circuit, each for 1 min. While breathing through a particular resistor, the patient was told whether the level of resistance was least, middle, or highest; each patient was coached until he was able to consistently rate a 30 cm H2O/L/s resistance as highest, 15 cm H2O/L/s as middle, and 5 cm H2O/L/s resistance as least. The ability to recognize and consistently rate each level of resistance was considered a prerequisite for progression to the second and third visits. After breathing through the last inspiratory resistor, the qualitative nature of the perceived difficulty in breathing was assessed using the questionnaire of Simon and colleagues (11) (Table 2). This assessment was undertaken to define the terminology used by the patients when describing the unpleasant sensation of breathing through a resistive load.
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The purposes of the second and third visits were to determine changes in diaphragmatic contractility and dyspnea sensation during resistive breathing after inhalation of albuterol or placebo. Patients received either four puffs of albuterol or four puffs of placebo via a spacer in a double-blind randomized fashion. To avoid the induction of twitch potentiation (16), patients were instructed to remain silent, breathe quietly, and not to cough or sigh for a period of 15 min after placement of all transducers. The patient was then instructed to breathe quietly through a mouthpiece for 5 min to acclimatize to the breathing circuit. Next, 10 nonpotentiated twitches were elicited by magnetic stimulation of the phrenic nerves. After another 5 min of resting breathing, at least five inspiratory capacity maneuvers were recorded followed by three forced vital capacity maneuvers. Five minutes later, the three linear resistors were separately introduced in random order in the inspiratory limb of the circuit, each for 1 min. Between each resistor, 30 s of resting breathing through the mouthpiece were allowed. Immediately before completion of each episode of resistive breathing, air hunger and effort sensations were assessed with the Borg scale. Resistive breathing was performed twice followed by five measurements of maximal transdiaphragmatic pressure. Immediately after each maximal maneuver, the phrenic nerves were stimulated twice at relaxed end-expiratory lung volume to obtain potentiated twitches (16).
During the third visit, a protocol identical to that of the second visit was performed using the alternative inhaler, i.e., albuterol if placebo had been used in preceding visit and vice versa.
Data Analysis
All signals were recorded and digitized at 2,000 Hz using a 12-bit analog-to-digital converter (DATAQ, Akron, OH) connected to a computer. Individual twitch responses were rejected from analysis according to previously described criteria (16, 17). Statistical analysis was performed using the software "SPSS for Windows, Release 7.5.1" (SPSS Inc., Chicago, IL). Paired t tests were utilized for parametric values in testing for significant difference between placebo and albuterol. All patients used the term "effort" to describe the sensation of breathing through the resistors (Table 2); accordingly, the dyspnea scores generated by the responses to the question "How much effort does your breathing require?" while patients breathed through the 30 cm H2O/L/s resistor were used in the data analysis. Wilcoxon's signed rank tests were used for change in dyspnea ratings after placebo versus albuterol inhalation. Regression analysis was employed to calculate the correlation coefficient between different variables.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Effects of Albuterol on Pulmonary Function and Dyspnea
Inspiratory capacity was 1.87 ± 0.71 L after inhalation of placebo, and it increased to 2.26 ± 0.74 L after inhalation of albuterol (p = 0.002). Likewise, forced expiratory volume in
one second increased from 0.97 ± 0.43 L after inhalation of
placebo to 1.11 ± 0.50 L after albuterol (p = 0.002). Patient
descriptors of respiratory sensation during resistive breathing
are listed in Table 2. When asked which term best described
the respiratory sensation during resistive breathing, all patients selected "my breathing requires effort," and nine of 11 patients selected "I feel a hunger for more air." While breathing
through linear resistors of 15 and 30 cm H2O/L/s, both effort
and air hunger scores were less after inhalation of albuterol
than with placebo; whereas breathing through a 5-cm H2O/L/s
resistor, dyspnea scores were similar after albuterol and placebo (Table 3). The decrease in dyspnea after albuterol was
related to the increase in inspiratory capacity (r = 0.62, p = 0.04), but not to the increase in FEV1 (r = 0.13, p = 0.72)
(Figure 1).
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Effect of Albuterol on Respiratory Muscle Output
Maximal transdiaphragmatic pressure was 92.4 ± 37.2 cm H2O
after inhalation of placebo, and it increased to 102.8 ± 37.2 cm H2O after inhalation of albuterol (p < 0.03) (Figure 2). The increases in maximal transdiaphragmatic pressure with albuterol
was related to the increase in inspiratory capacity (r = 0.70, p = 0.04) and to the decrease in dyspnea score (r = 0.64, p = 0.04) (Figure 3). Potentiated twitch transdiaphragmatic pressure was 21.6 ± 7.1 cm H2O after inhalation of placebo, and
it increased to 25.2 ± 7.6 cm H2O after inhalation of albuterol
(p < 0.02) (Figure 2). Recordings of potentiated twitch transdiaphragmatic pressure and inspiratory capacity in a representative patient are shown in Figure 4. The increase in potentiated twitch transdiaphragmatic pressure with albuterol was
related to the decrease in dyspnea score (r = 0.65, p = 0.04)
(Figure 3), and it tended to correlate with the increase in inspiratory capacity (r = 0.53, p = 0.12). Nonpotentiated twitch
transdiaphragmatic pressure was 15.4 ± 5.9 cm H2O after inhalation of placebo and 17.9 ± 7.3 cm H2O after inhalation of
albuterol (p = 0.075).
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Effect of Albuterol on Respiratory Mechanics and Respiratory Neuromuscular Performance
Dynamic compliance of the lung was 0.418 ± 0.222 L/cm H2O after inhalation of placebo and 0.458 ± 0.178 L/cm H2O after inhalation of albuterol (p = 0.16). Intrinsic positive end-expiratory pressure was 2.0 ± 1.4 cm H2O after inhalation of placebo and 1.4 ± 0.9 cm H2O after inhalation of albuterol (p = 0.14). The tidal change in esophageal pressure was 6.9 ± 2.8 cm H2O after inhalation of placebo, and it decreased to 5.8 ± 2.2 cm H2O after inhalation of albuterol (p = 0.04). The ratio of the tidal change in gastric pressure over that in transdiaphragmatic pressure tended to increase from 0.20 ± 0.22 after inhalation of placebo to 0.40 ± 0.37 after inhalation of albuterol (p = 0.085).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Albuterol relieved dyspnea and enhanced respiratory muscle output, which could be explained by lengthening of the diaphragm because of a decrease in lung volume. To our knowledge, this is the first investigation of the effect of inhaled albuterol on diaphragmatic contractility in patients with COPD.
Effect of Albuterol on Diaphragmatic Contractility
Albuterol produced an increase in maximal transdiaphragmatic pressure from 92.4 ± 37.2 to 102.8 ± 37.2 cm H2O. Albuterol also resulted in an increase in inspiratory capacity, indicating a decrease in the operating lung volume, which in
turn enhances the ability of inspiratory muscles to generate
pressure (18). In an attempt to avoid this anticipated confounding effect, we administered a non-2-bronchodilator, ipratropium bromide, 1 h before administration of albuterol or
placebo. Unfortunately, this strategy was not completely successful, and only three patients had inspiratory capacities after
albuterol and placebo that were within 5% of each other.
Over the range of inspiratory capacity, Braun and coworkers
(19) estimated that maximal transdiaphragmatic pressure increases by 2.1 cm H2O for each percent decrease in total lung
capacity. Employing this framework, the increase in inspiratory capacity with albuterol in our patients would be expected to result in a maximal transdiaphragmatic pressure of 102.6 ± 38.6 cm H2O
virtually identical to the recorded value of
102.8 ± 37.2 cm H2O (p = 0.95).
Potentiated twitch transdiaphragmatic pressure was also increased, from 21.6 ± 7.1 to 25.2 ± 7.6 cm H2O (p < 0.02), by albuterol. Over the range of vital capacity, Hamnegård and coworkers (20) found that potentiated twitch transdiaphragmatic pressure increases by 5.5 cm H2O for each liter decrease in lung volume. Using their framework, the anticipated mean potentiated twitch transdiaphragmatic pressure in our patients was 23.6 ± 8 cm H2O, similar to the recorded value of 25.2 ± 7.6 cm H2O (p = 0.16). These observations suggest that the increases in maximal transdiaphragmatic pressure and potentiated twitch transdiaphragmatic pressure after albuterol were due to the drug's effect on lung volume rather than a direct effect on diaphragmatic contractility. This likelihood is further supported by the data in the three patients who had equivalent lung volumes after the two treatments: albuterol and placebo resulted in similar values of maximal transdiaphragmatic pressure, 72.7 ± 26.7 and 70.9 ± 27.9 cm H2O, respectively, and of potentiated twitch transdiaphragmatic pressure, 19.1 ± 7.6 cm H2O and 19.4 ± 9.3 cm H2O, respectively.
In contrast with the increases in maximal and potentiated twitch transdiaphragmatic pressures, the change in nonpotentiated twitch pressure after albuterol inhalation did not reach statistical significance. The failure to detect an increase in nonpotentiated twitch transdiaphragmatic pressure may be due to inadvertent potentiation of the diaphragm during the placebo protocol in three patients; their nonpotentiated and potentiated twitch pressures had similar values. In the remaining eight patients, nonpotentiated twitch pressure was higher after albuterol than after placebo: 16.7 ± 7.1 and 14.2 ± 6.6 cm H2O, respectively (p < 0.02).
Indirect evidence (21, 22) supports our observation that 2-agonists, administered at customary doses, do not enhance diaphragmatic contractility. In a double-blind, placebo-controlled study in 11 healthy volunteers, tulobuterol, a 2-sympathomimetic agent, did not alter respiratory or limb muscle performance (21). In a double-blind, randomized crossover trial in
10 patients with normocapnic COPD, terbutaline did not alter maximal transdiaphragmatic pressure, FEV1, FRC, or dyspnea score (22). Diaphragmatic contractility was assessed by
volitional maneuvers, i.e., maximal voluntary efforts, in these
two studies. Maximal voluntary effort results from high motor
neuron frequencies (23) that occur only during phasic nonsustainable activity, and, thus, has limited clinical relevance.
Moreover, the recorded pressures may not reflect maximal muscle recruitment (24). Employment of phrenic nerve stimulation, as in this investigation, overcomes these problems in
the assessment of diaphragmatic contractility.
The dosage of albuterol in our study (360 µg, four puffs) is that recommended for the treatment of COPD (4), and it is likely to produce a peak serum concentration of 3 to 5 µg/L (25). The concentration of albuterol that induces enhanced contractility of the isolated diaphragm in a tissue bath is considerably higher (10 µg/L) (3). Although a higher dose of albuterol might elicit an inotropic effect on the diaphragm, the likely development of toxicity prohibits its clinical utility.
Effects of Albuterol on Pulmonary Function and Dyspnea
The increase in FEV1 with albuterol, although statistically significant, was less than that considered to reflect a clinically worthwhile response (26). In contrast, albuterol produced a relatively greater increase in inspiratory capacity: 390 ml or 24% of baseline. This difference in the magnitude of the response in FEV1 and inspiratory capacity to bronchodilator agents has been noted previously. In a study of 129 patients with obstructive airway disease, Ramsdell and Tisi (27) found that isoproterenol produced a change in inspiratory capacity alone in 46 patients, and changes in flow with or without change in inspiratory capacity in the remaining 83 patients. Despite the limited improvement in FEV1 after albuterol in our patients, dyspnea decreased; interestingly, the relief of dyspnea was related to the increase in inspiratory capacity and not to FEV1. In 21 patients with stable asthma undergoing bronchoprovocation with methacholine, Lougheed and colleagues (28) also noted that relief of dyspnea was related to an increase in inspiratory capacity. In 29 patients with COPD undergoing submaximal cycle exercise testing, O'Donnell and colleagues (29) noted that dyspnea ratings were more closely related to the change in inspiratory capacity than to any other variable. As shown in Figures 1 and 2, the mechanism accounting for the relief of dyspnea with change in inspiratory capacity is probably a length-based improvement in diaphragmatic contractility.
Dyspnea is thought to result from an imbalance between load on the respiratory system, i.e., impedance of the respiratory system, and respiratory muscle strength (30). A measure of the balance between diaphragmatic load and diaphragmatic strength is provided by relating the excursions in transdiaphragmatic pressure during tidal breathing to maximal transdiaphragmatic pressure. In our patients, albuterol produced a decrease in the ratio of tidal swing in transdiaphragmatic pressure to the maximal transdiaphragmatic pressure (0.24 ± 0.13 versus 0.19 ± 0.11, p = 0.004). Moreover, the percent change in the ratio of tidal swing in transdiaphragmatic pressure to the maximal transdiaphragmatic pressure was significantly correlated with dyspnea (r = 0.79, p = 0.004). Because both impedance and respiratory muscle output are coupled to changes in lung volume, our data cannot define the independent role of each factor in the development of dyspnea.
Effect of Albuterol on Respiratory Muscle Recruitment and Lung Mechanics
During resting breathing, albuterol produced a tendency towards an increase in the ratio of tidal change in gastric pressure over tidal change in transdiaphragmatic pressure from 0.20 to 0.40 (p = 0.085), suggesting a greater contribution by the diaphragm and a lesser contribution of the rib-cage muscles to tidal breathing (14). The increase in the aforementioned ratio could be due to enhanced diaphragmatic pressure output combined with a modest increase in dynamic compliance consequent to a shift of tidal breathing to a more compliant position on the pressure-volume curve of the respiratory system. A decrease in rib-cage muscle contribution to tidal breathing (31) may be partly responsible for relief of dyspnea with albuterol. A larger number of muscle spindles in rib-cage muscles (32) has been proffered as an explanation for the development of dyspnea with increased use of rib-cage muscles. Contrary to the notion that sensation evoked by a given respiratory load depends on the relative recruitment of the diaphragm and rib-cage muscles, Fitting and colleagues (33) noted that the magnitude of esophageal pressure was the main variable related to the sensation of inspiratory effort, irrespective of whether esophageal pressure was generated by the rib-cage muscles or the diaphragm. This possibility is supported by the recorded decrease in tidal swing in esophageal pressure after albuterol, which probably resulted from the combined tendencies for dynamic compliance to increase and positive end-expiratory pressure to fall with albuterol.
In conclusion, the improvement in dyspnea after inhalation of albuterol in patients with COPD was related to an increase in respiratory muscle output, which was primarily due to improvement in the length-tension relationship of the diaphragm rather than a direct improvement in its contractility.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Franco Laghi, M.D., Division of Pulmonary and Critical Care Medicine, Edward Hines Jr. VA Hospital, 111N, 5th Avenue and Roosevelt Road, Hines, IL 60141.
(Received in original form March 25, 1999 and in revised form June 14, 1999).
g%Dr. Hatipo lu was supported by the Chest Foundation of the American College of Chest Physicians.
Acknowledgments: Supported by grants from the Veterans Administration Research Service, the American Lung Association of Metropolitan Chicago, and the Gaylord and Dorothy Donnelly Foundation.
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References |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
REFERENCES
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