DOI 10.1378/chest.112.2.336 1997;112;336-340Chest

 Donald A. MahlerAlejandra Ramirez-Venegas, Joseph Ward, Timothy Lentine and COPDImproves Lung Function in Patients With Salmeterol Reduces Dyspnea and

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Salmeterol Reduces Dyspnea andImproves Lung Function in PatientsWith COPD*

Alejandra Ramirez-Venegas, MD; Joseph Ward, RCPT; Timothy Lentine, RCPT;and Donald A. Mahler, MD, FCCP

Study objective: To investigate the short-term effects of inhaled salmeterol on the perception ofdyspnea and lung function in patients with COPDDesign: Double-blind, crossover, randomized trial comparing inhaled salmeterol and inhaledplacebo over 4 h.Setting: Pulmonary function laboratory at university medical center.Patients: Sixteen patients with symptomatic COPD and at least 200-mL increase in FEV! afterinhalation of two puffs (180 jxg) of albuterol.Interventions: Visit 1 was used for familiarization. At visits 2 and 3 (2 to 3 days apart), patientsinhaled either two puffs of salmeterol (42 p,g) or placebo.Measurements and results: Lung function and dyspnea were measured at 0.5, 2, and 4 h afterinhalation of the study medication. Dyspnea was measured by the .5 to +5 category scale at restand by the 0 to 10 category-ratio scale while breathing through inspiratory resistances of 5, 15,and 30 cm H20/L/s. Age was 66±8 years (mean±SD). FEVX was 0.97±0.331 (51±13% predicted).There were significantly higher values for FEVX and FVC (at all time periods) and lower valuesfor functional residual capacity (at all time periods) and residual volume (at 4 h) with salmeterolthan with placebo. There were significantly lower dyspnea ratings on the .5 to +5 category scale(p=0.03 at 2 h and p=0.02 at 4 h) and for the mean dyspnea scores during resistive breathing withsalmeterol compared with placebo (p=0.002).Conclusions: Inhaled salmeterol reduced dyspnea, increased airflow, and reduced hyperinflationover 4 h in patients with symptomatic COPD. (CHEST 1997; 112:336-40)

Key words: chronic obstructive pulmonary disease; dyspnea; reduced hyperinflation; salmeterol

Abbreviations: 5R, 15R, and 30R=5, 15, and 30 cm H20/L/s resistance, respectively; CR-10=0 to 10 category-ratio;FRC= functional residual capacity; RV= residual volume; TLC=total lung capacity

CJ almeterol xinafoate, an inhaled long-acting f>2-^ adrenergic agonist, has been recommended forthe long-term, twice-daily maintenance therapy forpatients with asthma who require regular treatmentwith inhaled short-acting (^-agonists.12 Variousstudies have demonstrated that inhaled salmeterolprovided sustained bronchodilation and improvedsymptoms compared with inhaled albuterol or in¬haled corticosteroids in asthmatic patients.3-5 How¬ever, the possible benefits of salmeterol in patientswith COPD have not been established. Three pub¬lished studies have shown modest bronchodilation

*From the Department of Medicine, Dartmouth Medical School,Lebanon, NH.Supported by a grant from Glaxo Wellcome Inc.Manuscript received March 10, 1997; revision accepted May 9.Reprint requests: Donald A. Mahler, MD, FCCP, Section ofPulmonary and Critical Care Medicine.3-D, Dartmouth-Hitch¬cock Medical Center, One Medical Center Dr, Lebanon NH03756-0001; email: Donald.a.mahler@hitchcock.org

with salmeterol in patients with COPD.68 AlthoughUlrik8 reported a decrease in "symptom scores" withsalmeterol compared with placebo, the instrumentused for measurement had not been validated pre¬viously, symptoms were not differentiated, and theclinical difference of the symptom scores was diffi¬cult to interpret.The objective of this study was to investigate the

short-term effects of inhaled salmeterol on the per¬ception of dyspnea in patients with symptomaticCOPD. This is an important consideration becausethe major indication for the use of bronchodilatormedications in patients with COPD is to improvesymptoms. This statement is based on the observa¬tions that only oxygen therapy prolongs survival in

patients with hypoxemic COPD9 and that only smok¬ing cessation alters the accelerated decline in lungfunction.10 Therefore, current therapy should focuson symptom relief.

336 Clinical Investigations

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Our hypothesis was that salmeterol would reducethe sensation of dyspnea in the COPD population.We measured dyspnea using two different methods:the -5 to +5 category scale at rest and the 0-10category-ratio scale while patients breathed throughinspiratory resistances. To examine possible mecha¬nisms for any reduction in dyspnea, we measuredchanges in airway function and lung volumes in thisdouble-blind, crossover, randomized study that com¬pared inhaled salmeterol with inhaled placebo over a

4-h time period.

Materials and Methods

SubjectsSixteen patients with COPD as defined by the American

Thoracic Society11 were recruited for this study during a clinicallystable period from the outpatient pulmonary clinic at our insti¬tution. Inclusion criteria were as follows: a diagnosis of COPD; a

chief complaint of dyspnea for at least 3 months' duration; andevidence of airway reversibility defined by at least 200 mL and atleast 12% increase in FEVX after inhalation of two puffs (180 jxg)of albuterol. Exclusion criteria were any clinically significantcomorbid illness and inability to stop treatment with usualbronchodilator medications prior to testing.

Study DesignThe study was a randomized, double-blind, placebo-controlled

design approved by the Institutional Review Board. All patientssigned informed consent. Patients were instructed not to use anyinhaled bronchodilators for 6 h or theophylline for 24 h prior toeach visit.

Visit 1: The purposes of visit 1 were verification of inclusionand exclusion criteria, bronchodilator testing with albuterol, andfamiliarization with testing procedures. The severity of dyspneawas measured using the multidimensional baseline dyspneaindex.12Lung Function: Spirometry was performed using a testing

system (SensorMedics 2200; Yorba Linda, Calif). The highestvalues of FVC and FEVX were selected from a minimum of threeFVC maneuvers. At visit 1, spirometry was repeated 20 min afterinhalation of two puffs (180 jmg) of albuterol via metered-doseinhaler. Predicted normal values were taken from Crapo et al.13Maximal inspiratory mouth pressure was measured at functionalresidual capacity (FRC) using a pressure gauge connected to a

cylinder and mouthpiece.14 A minimum of five efforts was

performed until a reproducible maximal value was obtained.Predicted normal values were taken from Black and Hyatt.14FRC was measured by a pressure body plethysmograph (Sensor-Medics 2800 Autobox; Yorba Linda, Calif) using standard tech¬niques.15 At least three panting maneuvers were performed byeach patient, and the average of two to three consistent valueswas used. Total lung capacity (TLC) and residual volume (RV)were calculated by standard methods.

Resistance Breathing System: Next, in a seated position wear¬

ing noseclips, each patient breathed through a mouthpiececonnected to a two-way valve (Hans-Rudolph; Kansas City, Mo)and a resistive breathing system with linear resistances (using finewire mesh) of 5, 15, and 30 cm H20/L/s at flow rates of 0.5 to 2L/min. After the patient was breathing comfortably for 5 minwith no resistance, the 5 cm H20/L/s resistance (5R) was added

for 1 min. The patient was instructed to breathe normally and wastold that this resistance was "the lowest." The patient thenbreathed for 1 min with no resistance, and then the 15 cm

H20/L/s resistance (15R) was added. The patient was instructedthat the resistance was "in the middle." Finally, after breathingagainst no resistance for 1 min, 30 cm H20/L/s resistance (30R)was added for 1 min. The patient was told that the resistance was"the highest." The patient then breathed normally off the mouth¬piece for 5 min, and was asked to read the following writteninstructions while the 0 to 10 category-ratio (CR-10) scale16 wasdisplayed in front of the participant: "This is a scale for ratingbreathlessness. The number 0 represents no breathlessness. Thenumber 10 represents the strongest or greatest breathlessnessthat you have ever experienced. After each resistance you will beasked to point to a number with your finger which representsyour perceived breathlessness at that time. Use the writtendescription to the right of the number to help guide yourselection. I will say the number out loud in order to confirm yourchoice. You may have an even stronger or greater intensity ofbreathlessness than you have ever previously experienced. Youshould then point to the word 'maxima! if the severity is greaterthan 10. You can tell us this number after the mouthpiece hasbeen removed." The patient then breathed through the mouth¬piece with noseclips and each resistance (5R, 15R, and 30R) was

presented in random order for 1 min at two separate times. Afterbreathing for 1 min at each resistance, the patient, who was

blinded as to the level of resistance, rated the severity ofbreathlessness by pointing to a number on the CR-10 scale. A1-min period of breathing through the system but with no

resistance followed each added resistance.We then examined the ratings of breathlessness to verify that

each patient provided generally higher ratings for higher resis¬tances. For those individuals who did not provide consistent and"appropriate" ratings of breathlessness, we provided additionalfamiliarization with the three different resistances. In particular,we again presented the different resistances and informed thepatient as to whether the resistive was the lowest, in the middle,or the highest. Such additional familiarization/practice was per¬formed in 5 of the 16 patients. Except for one individual, allparticipants were able to rate consistently the severity of breath¬lessness as expected by the level of airway resistance at comple¬tion of visit 1.

Visit 2 (2 to 3 Days After Visit 1): Spirometry; lung volumes,and perception of dyspnea obtained from the resistance breath¬ing circuit (each resistance presented twice in random order for1 min) were measured at baseline. Then, each patient was

randomized to receive either two puffs (42 fxg) of inhaledsalmeterol or two puffs of inhaled placebo (the same contents as

the active medication but without salmeterol) from identicalappearing inhalers (provided by Glaxo Wellcome Inc; ResearchTriangle Park, NC) using an alternating schedule. At 30 min, 2 h,and 4 h after inhalation of the study medication, testing was

repeated in the same sequence.To consider any changes in the perception of dyspnea from

baseline, each person, starting with patient 5, was also asked to

give "a rating of the change in breathlessness" on the .5 to +5category scale17 at 30 min, 2 h, and 4 h compared to the baselinestate for that visit. These ratings were obtained prior to spirom¬etry. Patients were able to ambulate between testing periods, butthey were not allowed to use any medication or drink solutionscontaining caffeine or theobromine.

Visit 3 (2 to 3 Days After Visit 2): Identical testing was

performed at visit 3, although each patient received the alterna¬tive study medication.

CHEST/ 112/2 /AUGUST, 1997 337

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Statistical AnalysisBased on an SD of 0.5 for breathlessness ratings (on the CR-10

scale) from data by Kikuchi et al18 in normal individuals breathingthrough resistive loads, we calculated that 12 patients were

required to detect a paired difference of 2.0 with 80% power atan alpha of 0.05 (two-sided). One-way repeated measures analysisof variance was used to measure changes over time for salmeteroland for placebo for parametric values (eg, FVC and FEV,), whilethe Freidman test was used to examine changes over time fornonparametric values (eg, dyspnea ratings and lung volumes).For comparison of results between salmeterol and placebo at

the same time periods at visits 2 and 3, we used the paired t testfor parametric values and the Wilcoxon signed-rank test fornonparametric values.Spearman correlation coefficients were calculated for the

relationships between changes in dyspnea ratings (on the .5 to+ 5 category scale) and changes in physiologic variables, partic¬ularly FEVi, FVC, and FRC.

All values are presented as mean ±SD. A p value <0.05 was

considered significant.

Results

A total of 17 patients were recruited for the study.However, one patient exhibited inconsistent ratings ofdyspnea in response to resistance breathing at visit 1despite repeated efforts at familiarization and practice,and has not been included in the analysis. Anthropo¬metric and lung function values at visit 1 of the 16patients are reported in Table 1. As a group, there wasa modest range for dyspnea ratings and physiologicimpairment. All patients showed an increase of at least200 mL in FEV1 after inhalation of albuterol.

Results of airway function (FEV3 and FVC) andchanges in dyspnea ratings at visits 2 and 3 are shownin Table 2. There was a significant increase in FEVi(p<0.001), FVC (p<0.001), and dyspnea ratings on

the .5 to 4-5 category scale (p=0.02) over time withinhaled salmeterol, but no significant changes inthese variables with inhaled placebo. Comparison of

Table 1.Anthropometric and Lung Function Values in16 Patients With Symptomatic COPD*

Mean±SD RangeAge, yrHeight, cm

Weight, kgBDIFVC, L

FEVi, L

Post-BD FEV1? LPImax

65.6±8.3165.5±6.873.6+18.66.0±1.4

2.42±0.80(70±16)

0.97±0.33(51±13)1.23±0.3562.8±23.7(75±26)

50-77157-18051-1113-7

1.47-4.27

0.54-1.58

0.77-1.8030-100

*Number in parentheses is percent predicted value. BDI=baselinedyspnea index; BD=bronchodilator; PImax=maximal inspiratorymouth pressure.

Table 2.Results ofAirway Function and DyspneaRatings*

FEVl3 L FVC, LChanges in Dyspnea

(n = 12)'Salmeterol

Baseline30 min2h4h

PlaceboBaseline30 min2h4h

0.99±0.281.16±0.36*1.21±0.38f1.21±0.37f

1.00±0.291.01±0.291.01±0.320.99±0.34

2,59±0.762.93±0.87f2.97±0.84*2.96±0.82f

2.56±0.762.63±0.812.64±0.732.60±0.81

-1.8±1.7-2.8±1.8"-2.6+1.9*

-1.2±1.6-1.3±1.5-0.5±1.7

For results comparing salmeterol and placebo at the same time

periods.The changes in dyspnea ratings are from the .5 to +5 categoryscale17 compared to the baseline state.

fp<0.0013.*p=0.002.§p=0.005."p=0.03.

=0.02.

these variables at the same time period at differentvisits showed significantly higher values for FEVL (atall time periods) and significantly lower values fordyspnea ratings (at 2 and 4 h) with salmeterol.With regard to the values for lung volumes at the

four time periods, there were no changes in TLC.However, there were significant increases in FVC (atall time periods) and significant decreases in FRC (at

7.5

6.6

5.7

3.9

3.0

2.1

TLC8^.8z

Baseline30 min

2 hrs 4 hrs

o = Salmeterol . = Placebo

Figure 1. Mean values for lung volumes over time afterinhalation of salmeterol and placebo. See text for abbreviations.Asterisk=p<0.05 comparing salmeterol and placebo.

338 Clinical Investigations

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all time periods) and RV (at 4 h) with salmeterolcompared with placebo (Figure 1).Dyspnea ratings in response to breathing through

the resistances are reported in Table 3. The mean

dyspnea scores on the CR-10 scale during resistivebreathing (5R, 15R, and 30R) were significantlylower with inhaled salmeterol than with inhaledplacebo (p=0.002).There were no significant correlations between

the changes in dyspnea (.5 to +5 category scale)and changes in FEVX (rs= 0.11 to 0.39), changes inFVC (rs=-0.13 to 0.15), or changes in FRC(rs=0.11 to 0.35) at different time periods.

DISCUSSION

The major findings of this study in symptomaticpatients with COPD are that two puffs of inhaledsalmeterol (1) significantly improved airway function(increased FEVX and FVC) starting at 30 min andlasting for 4 h, (2) significantly reduced hyperinfla¬tion (FRC and RV), (3) significantly reduced theseverity of dyspnea as measured by the .5 to +5category scale at 2 and 4 h, and (4) significantlyreduced the perception of dyspnea in response to

breathing through inspiratory resistances.The increase in FEVX (mean change, +220 mL and

+22%) in our patients after salmeterol was modest andless than the +333 mL (+32%) improvement in FEVXreported by Cazzola and colleagues67 in patients with a

similar severity of COPD. However, Cazzola et al67used a holding chamber with the metered-dose inhalerto administer the salmeterol which may have deliveredmore aerosol to the lower respiratory tract. Certainly,the magnitude of bronchodilation observed with salme¬terol in COPD patients has been less than the responsein patients with asthma.34 Our results showed that peakbronchodilation occurred at 2 h after inhalation ofsalmeterol, whereas in two separate studies, Cazzola et

Table 3.Ratings of Breathlessness During Breathingat Three Levels of Resistance*

5R 15R 30R

30 minSP

2hSP

4hSP

1.5d1.7:!

1.4:!1.8:!

:1.21.4

1.21.8

1.7±1.21.9±1.7

3.3±1.63.5±1.9

3.6±2.23.8±2.2

3.5±2.24.2±2.6

5.5:6.2=

5.7d6.4 =

6.2:!6.4:!

:2.4=2.7

=2.8=2.8

=2.7= 3.2

*Values are mean±SD for 16 patients. S=salmeterol; P=placebo;R=airway resistance in cm H20/L/s. p=0.002 comparing mean

individual ratings for salmeterol vs placebo at all resistances.

al6-7 reported peak bronchodilation occurred at 2 h andat 5 h after administration in patients with COPD.However, the differences in spirometric values at 2 and5 h were small.67We also examined changes in lung volumes after the

study medications. There were gradual, but consistentdecreases in both FRC and RV over the 4-h studyperiod with salmeterol. Compared with results of pla¬cebo, the changes in FRC with salmeterol were signif¬icant starting at 30 min and lasting for 4 h, while thedecrease in RV was significant only at 4 h.Any improvement in airflow and a concomitant

reduction in hyperinflation may be of clinical benefitfor patients with COPD.19 In this study, we mea¬

sured the sensation of breathlessness with two dif¬ferent approaches. We used the .5 to +5 categoryscale as described by O'Donnell et al17 to measure

changes in perception from the baseline state. Therewere significantly greater reductions in dyspnea withsalmeterol compared with placebo at 2 and 4 h. It isinteresting that the reduction in dyspnea occurred atthe same time as peak bronchodilation was observedafter inhalation of salmeterol. However, there were

no significant correlations between changes in dys¬pnea and changes in physiologic variables. This was

not totally surprising because dyspnea and lungfunction represent different constructs and correlateonly modestly in COPD.2021

In addition, we examined the perception of breath¬lessness as provoked by patients breathing throughinspiratory resistances. This technique is one approachused to stimulate dyspnea to examine the severityand/or mechanisms contributing to the sensation ofbreathlessness. We selected this method based on thestudy by Kikuchi et al18 which showed that patientswith a history of near-fatal asthma had lower dyspneascores during breathing through inspiratory resistancescompared with normal subjects. We used the same

range of airway resistance (5 to 30 cm H20/L/s) as

described by Kikuchi et al,18 and were interested to

investigate whether this approach could detect changesin perception of dyspnea with the expected physiologicimprovements after inhaled salmeterol. Although theoverall results showed a significant decrease in breath¬lessness after salmeterol compared with placebo, theabsolute differences were small. The mean differencebetween the two treatments was approximately 0.5units on the CR-10 scale at 30R. Nevertheless, theoverall results using the two measurement techniquesshowed consistent improvement in dyspnea with sal¬meterol over a 4-h measurement period.We attempted to examine possible mechanisms for

the expected improvement in breathlessness with sal¬meterol. Certainly, the most important mechanicalabnormality in COPD is expiratory flow limitation.However, a major consequence ofairflow obstruction is

CHEST/112/2/AUGUST, 1997 339

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hyperinflation; this results in an inspiratory thresholdload (to overcome the inward elastic recoil of the lung)and compromises the ability of the diaphragm to

generate pressure (due to shortening of the verticalmuscle fibers).19 O'Donnell and Webb22 have demon¬strated the importance of dynamic hyperinflation in

contributing to exertional breathlessness in patientswith COPD. From a therapeutic perspective, anyreduction in the resistive or elastic load associated withbreathing should relieve dyspnea. In our study, inhaledsalmeterol caused modest bronchodilation, but thechanges in dyspnea were not significantly related to

changes in FEVX or FVC. Previous studies have alsodemonstrated improvements in dyspnea in the pres¬ence of small increases in FEVj.23'24 More likely, thereduction in breathlessness in this setting may be linkedto reduced lung hyperinflation. Although we observedsignificant reductions in FRC and RV with salmeterol,there were no significant correlations between mea¬

sures of lung volumes and breathlessness. However, itis possible that improvement in dyspnea widi salmet¬erol may be due to the combined benefits of bron¬chodilation (reduced resistive load) and reduced hyper¬inflation (reduced elastic load and/or improveddiaphragm function). Direct measurement of the in¬

spiratory threshold load and/or diaphragmatic functionmay be required to further explore possible mecha¬nisms for relief of dyspnea with salmeterol.

In summary, inhaled salmeterol increased airflow,reduced hyperinflation, and improved the severity ofbreathlessness over a 4-h period in patients with symp¬tomatic COPD. This group was selected based on

bronchodilator responsiveness (at least 200 mL in¬crease in FEVX) to inhaled albuterol. The improvementin dyspnea with salmeterol has major importance be¬cause relief ofsymptoms is the primary focus oftherapyin COPD. In order to determine the role of inhaledsalmeterol in the treatment of COPD, additional stud¬ies are necessary to investigate the long-term effects ofsalmeterol on physiologic and clinical outcomes as wellas the efficacy of salmeterol compared with standardbronchodilator medications used to treat COPD.

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340 Clinical Investigations

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DOI 10.1378/chest.112.2.336 1997;112; 336-340Chest

Donald A. MahlerAlejandra Ramirez-Venegas, Joseph Ward, Timothy Lentine and

Patients With COPDSalmeterol Reduces Dyspnea and Improves Lung Function in

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