TheAdditive Effect of Theophylline on a Combination Inhaled … · 2017-06-27 · different between theophylline and placebo periods. Nevertheless, eightpatients reported a subjective

The Additive Effect of Theophylline on aHigh-Dose Combination of InhaledSalbutamol and Ipratropium Bromide inStable COPD*Koichi Nishimura, MD; Hiroshi Koyama, MD; Akihiko Ikeda, MD;Naoharu Sugiura, MD; Kazuo Kawakatsu, PhD;and Takateru Izumi, MD; FCCP

Study objective: To determine the additive effect of oraltheophylline in patients with stable COPD who receivedboth inhaled salbutamol, 400 jig, and ipratropium bro-mide, 80 gg, four times daily administered with ametered-dose inhaler.Design: Twenty-four male patients with stable COPD(FEVI, 0.96 + 0.43 L; 36.8 ± 17.0 percent predicted[% pred]) completed a randomized, double-blind, pla-cebo-controlled crossover trial with oral theophylline for4 weeks.Measurements and results: The average serum theo-phylline level was 15.0±5.5 ,g/mL during treatment.On the whole, without inhalation of bronchodilators,FEV1 was 0.93 ± 0.42 L during the placebo period and1.00 + 0.43 L (significantly different from placebo;p<0.01) during the theophylline period. At 15 and 60 minafter inhalation of salbutamol, 400 jig, and ipratropium,80 ,ug, the FEV1 with placebo was 1.12±0.43 L and1.14 ± 0.46 L, respectively, and the FEV1 with theophyl-line was 1.18 ± 0.45 L (p<0.01) and 1.20 ± 0.47 L (p<0.01),respectively. Daily peak expiratory flow rate also im-proved. Daily symptom scores were not significantlydifferent between theophylline and placebo periods.Nevertheless, eight patients reported a subjective bene-fit during the theophylline administration period, and

The bronchodilating effect of oral theophylline isinferior to that of inhaled bronchodilators.1'6

Therefore, for patients with stable chronic obstruc-tive pulmonary disease (COPD), recent therapeuticrecommendations suggest that theophylline shouldbe used only as a third-choice drug if combined in-haled anticholinergic agent and inhaled f2-agonistfail to improve a patient's condition.7-9 However,some controversy exists as to whether the effect oftheophylline is additive on that of the inhaled bron-chodilators. Another complicating factor is that a

*From the Chest Disease Research Institute, Kyoto University,Kyoto, Japan.Supported in part by a research grant from Smoking ResearchFoundation in Japan.

Manuscript received December 20, 1993; revision accepted Au-gust 5, 1994.Reprint requests: Dr. Nishimura, 2nd Department of Medicine,Chest Disease Research Institute, Kyoto University, 53 Kawara-machi, Shogoin, Sakyoku, Kyoto 606, Japan

they were thus considered subjective responders. WhileFEV1 after inhalation was significantly improved dur-ing the theophylline periods in subjective responders(change in FEV1 between theophylline and placebotreatment 15 min after inhalation, 3.1 %pred; 60 min,3.5 %pred), postbronchodilator FEV1 was not signifi-cantly different between the placebo and theophyllineperiods in subjective nonresponders (15 min, 1.7 %pred;60 min, 1.6 %pred).Conclusions: On the whole, theophylline has a smallbronchodilating effect but does not improve the symp-toms of patients with stable COPD. However, one thirdof patients with COPD may respond subjectively totheophylline. The additive bronchodilating effect oftheophylline may be related to the symptomatic im-provement in subjective responders.

(Chest 1995; 107:718-23)

FEV4=forced expiratory volume in 1 s; FVC=forced vitalcapacity; MDI=metered-dose inhaler; PEFR=peak expi-ratory flow rate

Key words: bronchodilator; chronic obstructive pulmo-nary disease (COPD); ipratropium bromide; salbutamol;theophylline

single dose of theophylline may not predict theresponse to long-term bronchodilator therapy. Sev-eral clinical trials that compared over several weekstheophylline, inhaled 02-agonist, and the combina-tion of these drugs showed additive effects for thesetwo drugs.10-18

Anticholinergic agents are often used as the first-line therapy in patients with stable COPD,3"922 andcombined inhalation of an anticholinergic agent anda 32-agonist may be more effective than inhalation ofeither drug alone.23-26 From the perspective ofpatient medical compliance, the dosage of a singleinhaled bronchodilator should be maximized beforea second agent is added.7-9 Nevertheless, severalstudies that examined the effect of theophylline incombination with an inhaled bronchodilator wereperformed using suboptimal doses of the inhaledbronchodilator.10'17 Our earlier study demonstrated

Effect of Theophylline, Salbutamol, and Ipratropium Bromide on COPD (Nishimura et a!)718

Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21710/ on 06/27/2017

that oral theophylline had an additive bronchodilat-ing effect when used with inhaled salbutamol, 200,ug, and ipratropium bromide, 40 Ag, but improve-ments in the symptoms were not observed.27 If largerdoses of the /2-agonist and anticholinergic agent hadbeen used, the additive bronchodilator effect oftheophylline may not have occurred.The purpose of the present study was to determine

the additive effect of oral theophylline in patientswho received a high-dose combination of inhaledanticholinergic agent and inhaled /32-agonist. Pa-tients with stable COPD completed a randomized,double-blind, placebo-controlled crossover trial withoral theophylline for 4 weeks. To ensure that suffi-cient bronchodilators were inhaled to achieve nearmaximum bronchodilating effect, all patients con-tinued to take both salbutamol, 400 ,g, and ipratro-pium bromide, 80 ,tg, using a metered-dose inhaler(MDI) with a spacer device four times a day through-out the study period.

MATERIALS AND METHODSPatient Selection

Thirty-two male patients with stable COPD as defined by theAmerican Thoracic Society28 were recruited from the patientswho regularly visited the outpatient clinic at the Chest DiseaseResearch Institute, Kyoto (Japan) University, over several months.We considered patients with no acute exacerbation of airflowobstruction within the preceding 3 months as having stableCOPD. The inclusion criteria for entry into the study were asfollows: age older than 55 years; a history of cigarette smoking ofmore than 20 pack-years; chest radiograph showing hyperinfla-tion with or without a vascular deficiency pattern suggestive ofpulmonary emphysema; a best postbronchodilator ratio of theforced expiratory volume in 1 s (FEV1) to the forced vital capac-ity (FVC) of less than 70%; and an FEV, of less than 80% of thepredicted value. We excluded patients with any history sugges-tive of asthma, heart disease, or any other illness. Patients treatedwith inhaled or systemic steroids in the preceding 3 weeks werealso excluded.To familiarize patients with the inhalation technique, they re-

ceived detailed instructions on the use of an MDI and a spacerdevice (InspirEase).29 The canister was activated, the spacer witha MDI attached was held in the mouth, and after the patient hadexhaled to functional residual capacity, a very slow inhalation wasmade until total lung capacity was reached. At this point thebreath was held for at least 5 s. Patients with a poor techniquewere excluded from the study. Written informed consent wasobtained from each patient.

Study Design

On the first day of the study, all patients underwent baselinepulmonary function tests 12 h after withdrawal of bronchodila-tors. Functional residual capacity was determined by bodyplethysmography (MBR-600, Nihon Kohden Co, Tokyo, Japan),and residual volume was calculated as functional residual capac-ity minus expiratory reserve volume measured by spirometrictesting. Total lung capacity was determined as the sum of vitalcapacity and residual volume. Static compliance and airway re-sistance were also measured by body plethysmography. The dif-fusing capacity of the lung for carbon monoxide was measured bythe single-breath technique (Chestac-65, Chest, Tokyo). Revers-

ibility of FEV, to 400 gg of salbutamol was measured after thesepulmonary function tests. The drug was administered in fourpuffs from a MDI using the spacer device and spirometry wasmeasured before and 15 min after inhalation.

Sustained-release theophylline and matching placebo (Rh6ne-Poulenc Rorer Japan, Tokyo) were each administrated for a4-week period in a randomized, double-blind, placebo-controlledcrossover fashion (Fig 1). The daily doses of theophylline werepredetermined to provide average serum concentrations of morethan 10 ,g/mL and matching quantities of placebo were given.All of the patients continued to inhale both salbutamol (400 ,ug infour puffs) and ipratropium bromide (80 ,ug in four puffs) usingan MDI four times a day throughout the study period. Treatmentwith all other drugs was withheld for at least 2 weeks prior to andduring the study period.The patients visited the outpatient clinic around the same time

at 4-week intervals. Inhalation was stopped at least 12 h beforeevery visit. To ensure that the drugs were administered duringdeep inspirations, the inhalation technique was carefully observedby the same physician (K.N.). This physician also carefullyobserved all of the spirometric measurements. Blood samples forthe assay of theophylline were collected at each visit and storeduntil the study was completed. Serum theophylline concentrationswere determined by fluorescence polarization immunoassay usingan analyzer (TDx, Dainabot, Tokyo).

Outcome Measures

Acute bronchodilator responses to the inhaled bronchodilatorswere measured at every visit to the clinic. Spirometry was assessedbefore, and 15 and 60 min after the inhalation of both salbutamol,400 Ag (four puffs), and ipratropium bromide, 80 jug (four puffs),using an MDI with a spacer device. Three consecutive flow-vol-ume curves were recorded, according to the method described inthe American Thoracic Society 1987 update,30 which requires thepatient to stand during spirometry measurements. The spirome-ter (Autospiro AS-600, Minato Medical Science, Osaka) was cal-ibrated with a 2.0-L syringe before every measurement. Thelargest FEV, and the largest FVC among three maneuvers wereanalyzed. The predicted values of FEV 1 and FVC were calculatedaccording to the Japan Society of Chest Diseases' proposal.3'

Daily home measurements of peak expiratory flow rate (PEFR)were obtained during the entire study period before and 15 minafter each inhalation of the bronchodilator four times a day us-ing a flowmeter (Mini-Wright Peak Flow Meter, Airmed, Clem-ent Clarke, London). Patients recorded the greatest value of threereadings. Symptoms of cough, sputum, wheezing, and shortnessof breath, rated on a scale of one to four (1=minimum to 4=se-

salbutamol 400pg+ ipratropium bromide 80pg q. i.d.

1 Theophylline Placebo |-

N"A Placebo Theophylline

randomizato cross-over Fend of study

assessment of PEFR| and symptom scores

0 1 2 3 4 5 6 7 8 weeks

FIGURE 1. Study design for examining the effects of adding oraltheophylline to salbutamol, 400 Mg, and ipratropium bromide, 80jig, in patients with stable COPD.

CHEST / 107 / 3 / MARCH, 1995 719


vere), were noted in a diary, and side effects were also recordedduring the entire study period.27 The PEFR readings, dailysymptom scores, and side effects were assessed for the last 14 daysof each 4-week period.

At the end of the study, all patients were asked to compare thetwo different treatment periods with respect to clinical well-be-ing. If a patient did not find any difference in symptoms betweenthe two treatment periods, he was considered a subjective nonre-sponder. If a patient felt much better during one side treatmentperiod and much worse during another treatment period and hisselection was compatible with theophylline treatment after theregimens were revealed, we defined him as a subjective re-sponder. If his preference did not correspond to the theophyllinetreatment after the regimens were revealed, he was also definedas a subjective nonresponder.

Statistical AnalysisAll data are expressed as the mean ± SD. The significance of

differences between values observed during treatment withtheophylline and the placebo was determined by repeated mea-sured analysis of variance. When appropriate, means were com-pared using the paired t test (two-tailed). Daily symptom scoreswere analyzed using nonparametric analysis of variance andWilcoxon's signed ranked test. Comparisons of baseline charac-teristics between responders and nonresponders were performedby unpaired Student's t test for normally distributed continuousdata, Mann-Whitney U test for nonparametric data, and x2 testfor categorical data. For all tests, a p value <0.05 was consideredto be statistically significant.

RESULTS

Seven patients who began the study did not finishit. One patient was withdrawn because he com-plained of urinary tract infection apparently unre-lated to the study. Four patients dropped out of thestudy because of exacerbation due to respiratory tractinfection: two during the theophylline period andtwo during the placebo period. While receivingtreatment with theophylline, two patients discontin-ued its use because of gastrointestinal side effects.Twenty-five male patients completed the entirestudy. Since theophylline was not detected in theblood during the theophylline period in one patient,he was excluded from the data analysis. Conse-quently, a total of 24 patients were evaluated.The baseline clinical data for the 24 patients are

shown in Table 1. The average patient was elderlywith a significant smoking history, severe airflowlimitation, and hyperinflation. Three patients werecurrent smokers and 21 patients were former smok-ers. The doses of theophylline/placebo administereddaily were 400 ,ug for 1 patient, 600 mg for 20patients and 800 mg for the remaining 3. Theophyl-line was not detected in the blood during the placeboperiod, but during active treatment serum theophyl-line averaged 15.0 ± 5.5 ,ug/mL. There were onlyfour patients with serum theophylline concentrationsof less than 10 gg/mL (9.6, 7.9, 6.8, and 6.7 ,tg/mL).

Acute bronchodilator responses to both inhaledsalbutamol, 400 ,ug, and ipratropium bromide, 80 ,ug,were measured at every visit to the clinic during the

placebo and theophylline periods. Without inhala-tion of bronchodilators, FEV1 was 0.93 ± 0.42 Lduring the placebo period and 1.00 ± 0.43 L (signif-icantly different from placebo; p<0.01) during thetheophylline period. At 15 and 60 min after inhala-tion of salbutamol, 400,g, and ipratropium bromide,80 ,Ag, the FEV1 with placebo was 1.12±0.43 L and1.14±0.46 L, respectively, and the FEV1 with theo-phylline was 1.18 ± 0.45 L (p<0.01) and 1.20 ± 0.47L (p<0.01), respectively. The FVC was not signifi-cantly different between the placebo and theophyl-line periods before and 15 and 60 min after the in-halation of the bronchodilating agents. Both prein-halation and postinhalation values of daily PEFRwere significantly higher during the theophyllineperiod than during the placebo period (both p<0.01).No significant alteration of cough, sputum, wheezing,or shortness of breath was observed throughout thedifferent phases of treatment (Table 2).

At the end of the study period, 15 patients did notrecognize any symptomatic differences during thetwo crossover periods with active or placebo admin-istration (subjective nonresponders). Nine patientsreported symptomatic improvement during one ofthe two treatment periods. Since one of nine patientspreferred the placebo period to the theophylline pe-riod, he was classified as a subjective nonresponder.The other eight patients were classified as subjectiveresponders.

For these eight subjective responders, all the val-ues of FEV1 measured before and 15 and 60 min af-ter the inhalation were significantly different be-tween the placebo and theophylline periods (change

Table 1-Baseline Clinical Data for 24 PatientsWho Completed the Study*

Mean SD Range

Age, yr 65.3 4.7 55-73FEV1, L 0.96 0.43 0.36-1.77FEV1, %pred 36.8 17.0 14.9-72.1FEV1/FVC, % 38.4 9.0 23.8-57.3VC, L 2.91 0.62 1.98-4.36%VC, % 83.0 17.9 52.9-122.1Dco, mL/min/mm Hg 18.1 5.0 10.2-26.7Dco, %pred 74.4 19.8 43.3-107.3Dco/VA, mL/min/mm Hg/L 3.66 1.11 2.09-6.07TLC,f L 8.05 1.06 5.84-10.03TLC,f %pred 121.2 14.2 100.9-155.4Cst,4 L/cm H20 0.39 0.19 0.19-0.86Raw,t cm H20/L/s 5.74 1.53 3.43-8.54FEV1 reversibility, %initial 121.1 14.5 93.5-151.7FEV1 reversibility, change %pred 6.3 4.6 -4.0-11.5Blood eosinophils, /mm3 181 92 51-354

*VC=vital capacity; Dco=diffusing capacity for carbon monoxide;TLC=total lung capacity; Cst=static compliance; and Raw=airwayresistance; SD=standard deviation.tNot measured in one patient because of severe airflow limitation.INot measured in four patients because of severe airflow limitation.

Effect of Theophylline, Salbutamol, and Ipratropium Bromide on COPD (Nishimura et al)720


Table 2-Comparison of the Results of Spirometry on the Final Day of Each Treatment Period*

Placebo Theophylline p Value

FEV1, %predBefore 35.7 ±16.9 38.5±17.5 <0.0115 min 42.8 ±17.2 45.0+17.9 <0.0160 min 43.7+18.3 45.9±18.6 <0.01

FVC, %predBefore 69.3 ±21.6 72.6+18.8 NS15 min 84.3 ±18.2 83.8 +21.0 NS60 min 85.3±19.5 85.4+ 22.4 NS

Daily PEFR, L/minBefore 276 + 86 291+ 89 <0.01After 310+89 325±90 <0.01

Cough (l=minimum to 4=severe) 1.8 1.6 NSSputum (l=minimum to 4=severe) 1.4 1.4 NSWheeze ( =rminimum to 4=severe) 1.7 1.6 NSDyspnea (l=minimum to 4=severe) 2.1 2.1 NSTotal symptom score (4-16) 7.0 6.7 NS

*Daily home peak expiratory flowrate (PEFR) and symptom scores were obtained during the last 14 days of each treatment period. NS=not sig-nificant.

in FEV1 between theophylline and placebo treat-ment 15 min after inhalation, 3.1 % pred; 60 min, 3.5%pred) (Table 3). However, for 16 subjective nonre-sponders, FEV1 values were not significantly differ-ent between the placebo and theophylline periods at15 and 60 min after inhalation (15 min, 1.7 %pred;60 min 1.6 %pred), although theophylline signifi-cantly improved FEV1 at the preinhalation evalua-tion. When FVC, daily home PEFR, and symptomscores were analyzed separately for subjective re-sponders and for nonresponders, the results weresimilar to those obtained when all patients weregrouped together. Furthermore, none of the baselineclinical characteristics shown in Table 1 or the serumtheophylline level was significantly different be-tween subjective responders and nonresponders.

Sixteen patients (67%) complained of gastrointes-tinal side effects while receiving theophylline and 10patients (42%) reported similar adverse effects duringplacebo administration. By counting the number ofdays that gastrointestinal side effects were reported,we found that theophylline was significantly associ-ated with anorexia or nausea when compared with

Table 3-FEV1 in Subjective Responders andNonresponders Before and 15 and 60 min After

Inhalation of Salbutamol, 400 lug, and IpratropiumBromide, 80 ,tg, on the Final Day of Treatment With

Either Theophylline or a Placebo

Placebo Theophylline p Value

Responders (n=8)Before 42.7 ± 20.9 46.2 + 21.3 <0.0515 min 50.1±23.2 53.2±23.0 <0.0560 min 50.8±24.8 54.3±24.3 <0.05

Nonresponders (n=16)Before 32.2±14.0 34.6±14.4 <0.0515 min 39.2±12.7 40.9±13.8 NS60 min 40.2+ 13.6 41.8± 14.2 NS

placebo administration (p<0.05). Three patients(13%) experienced irritability during theophyllinetreatment, whereas 2 (8%) reported a similar com-plaint during placebo treatment.

DISCUSSION

The present report describes the first study (to ourknowledge) that examined the additive effect oftheophylline in patients with stable COPD who pre-sumably received sufficient doses of both inhaledanticholinergic agent and inhaled 32-agonist. Ourresults indicate that the bronchodilating effect oftheophylline, when used in combination with salbu-tamol, 400 ,tg, and ipratropium bromide, 80 ,ug, issmall, but significant. This small additive bronchod-ilating effect does not result in symptomatic improve-ment. Although one third of patients reported symp-tomatic benefits with the administration of oraltheophylline, none of the variables analyzed allowedus to predict these subjective responders.Some clinical trials, which have compared the ad-

ditive effect of combined therapy with theophyllineand inhaled bronchodilators over several weeks, havereported contradictory results. Since both inhaledf32-agonists and anticholinergic agents induce dose-dependent bronchodilation in patients with stableCOPD,32-34 an additive effect of theophylline can bedetermined only if these drugs are used at maximaldoses. Some studies used a fl-adrenergic bronchodi-lator administered in two puffs from an MDI, andothers prescribed a heterogeneous drug mixture to setthe background during the study. We used 400 Ag ofsalbutamol and 80 Ag of ipratropium bromide con-tinuously in the present study. Since these doses aredouble the clinically recommended doses, we believethat near maximum bronchodilation was achieved.35

CHEST / 107/3 / MARCH, 1995 721


Dose-dependent bronchodilation also makes itdifficult to discriminate between irreversible and re-versible airflow limitation. Although reversibility inFEV1 was not included as an entry criterion in thepresent study, we carefully selected patients withlong-standing COPD. All the patients had been fol-lowed up over several months in our hospital. At thestart of this study, we measured bronchodilatorresponses after the inhalation of salbutamol, 400 ,tg,using an MDI. Although FEV1 after bronchodilatorinhalation was on average 121% of the prebroncho-dilator value, similar bronchodilator responses havebeen reported in some previous studies on COPD.3234The clinical and physiologic improvements notedwith inhaled bronchodilators are usually associatedwith the small but statistically significant increases inFEVI.

Oral theophylline has been used for several de-cades as a bronchodilator. In addition, theophyllinemay improve diaphragmatic contractility36'37 andrespiratory muscle performance,38 produce a sus-tained but modest enhancement of cardiac biven-tricular performance,39 and reduce the dyspnea sen-sation.40 However, none of our patients, even thosewho felt symptomatic benefit from theophylline(subjective responders), reported significant changesin their daily symptom scores. To our knowledge,there has been little evidence that oral theophyllinetreatment improved daily symptom scores.27'41-43Daily symptom scores, such as the four-grade scorethat we used, may not be sensitive enough to moni-tor patient symptoms adequately. Therefore, the as-sessment of symptoms and subjective improvementcould have been strengthened in the present study byusing objective measurements of the patient's exer-cise tolerance such as a 6-min walk or a Borg or vi-sual analog scale with standardized tasks to evaluatedyspnea on exercise. The inclusion of a quality-of-lifescale to determine if any improvement was counter-balanced by adverse effects would have been useful.

Kirsten et a144 conducted a study on theophyllinetherapy withdrawal and found that about half of thepatients with severe COPD can be considered theo-phylline responders. They also suggested that theclinical effectiveness of this drug cannot be attributedexclusively to bronchodilation. In the present study,while FEV1 after inhalation was significantly im-proved during periods of theophylline treatment insubjective responders, postbronchodilator FEV1 wasnot significantly different between the placebo andtheophylline periods in subjective nonresponders.This finding suggests that the additive bronchodilat-ing effect of oral theophylline is related to thesymptomatic improvement in subjective respondersand also suggests that daily symptom scores used inthe present study did not reflect the symptomatic

improvement in subjective responders.Filuk et a14 reported that inhaled salbutamol and

intravenous aminophylline are additive as broncho-dilators in patients with COPD. However, Georgop-oulos et al45 found that intravenous salbutamol andaminophylline did not have a significant additivebronchodilating effect. The latter authors suggestedthat the distribution of the drugs could be differentwith inhaled and intravenous routes of administra-tion.45 Thus, differential distribution of inhaled andorally administrated drugs may account for our ob-servation of an additive effect of oral theophyllinewhen used in conjunction with a high dose of inhaledbronchodilators.

In conclusion, since theophylline has a smallbronchodilating effect but does not improve thesymptoms of patients with stable COPD, the useful-ness of oral theophylline in combination with a highdose of inhaled bronchodilators is doubtful. How-ever, when theophylline is used with adequateamounts of inhaled bronchodilators, our results sug-gest that one third of the patients with stable COPDmay respond to theophylline. The additive bron-chodilating effect of oral theophylline may be relatedto this symptomatic improvement in subjective re-sponders. Since gastrointestinal side effects are fre-quently associated with theophylline administration,not all patients with COPD should receive theophyl-line and continuation of theophylline treatmentshould be considered only for patients who feel bet-ter. For individual patients with COPD, it would beworthwhile to perform a trial with theophylline to seeif symptomatic improvement occurs before theo-phylline is continuously prescribed.ACKNOWLEDGMENTS: The authors thank Rhone-PoulencRorer Japan Inc for providing theophylline and matching pla-cebo. The authors also wish to thank Anders G. Eklund, MD,(Karolinska Hospital, Stockholm) for checking our manuscript.

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