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(Chest. 1999;115:376-382.)
© 1999 American College of Chest Physicians

Effects of Inhaled Bronchodilators on Pulmonary Hemodynamics at Rest and During Exercise in Patients With COPD*

Shunichi Saito, MD; Kenji Miyamoto, MD; Masaharu Nishimura, MD; Akira Aida, MD; Hiroshi Saito, MD, FCCP; Ichizo Tsujino, MD and Yoshikazu Kawakami, MD, FCCP

* From the First Department of Medicine (Drs. Saito, Nishimura, Aida, Saito, Tsujino, and Kawakami), School of Medicine; and the Department of Physical Therapy (Dr. Miyamoto), College of Medical Technology, Hokkaido University, Sapporo, Japan.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Introduction: Inhaled anticholinergic drugs are often recommended for use as a first-line therapy for patients with COPD because they provide similar or more effective bronchodilating actions, as well as fewer side effects. It is not known, however, which class of bronchodilators is more advantageous for pulmonary hemodynamics, particularly during exercise.

Objectives: To compare the effects of oxitropium and fenoterol on pulmonary hemodynamics in patients with COPD at rest and during exercise.

Patients: The study participants consisted of 20 consecutive male patients with stable COPD, a mean (± SD) age of 68 ± 8 years old, and an FEV1/FVC ratio of 47.5 ± 10.0%.

Methods: Eleven patients inhaled two puffs of oxitropium, and nine patients inhaled two puffs of fenoterol. Seven members of each group performed incremental exercise using a cycle ergometer. The hemodynamic measurements with right heart catheterization were performed by taking the average of three consecutive respiratory cycles before and after the administration of inhaled bronchodilators at rest and during exercise.

Results: At rest, despite a similar improvement of spirometric data with the two drugs, fenoterol, not oxitropium, caused significant increases in heart rate and cardiac output, a decrease in pulmonary vascular resistance, and a deteriorated PaO2. During exercise, however, both drugs similarly attenuated elevations in the mean pulmonary arterial pressure (40 ± 12 to 38 ± 10 mm Hg by oxitropium, and 41 ± 9 to 36 ± 9 mm Hg by fenoterol), the mean pulmonary capillary wedge pressure, and the mean right atrial pressure.

Conclusion: Our findings indicate that both classes of bronchodilators are equally beneficial in the attenuation of right heart afterload during exercise in patients with COPD.

Key Words: exercise • fenoterol • oxitropium • pulmonary arterial pressure


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The choice between anticholinergic drugs and ß-agonists as a first-line therapy for patients with COPD is still a matter of debate. Although inhaled anticholinergic drugs are currently used more frequently than inhaled ß-agonists, because of the similar1 ,2 ,3 or more effective4 ,5 ,6 ,7 bronchodilating actions and fewer side effects of the former,6 ,8 it is not known which class of bronchodilators is more advantageous for pulmonary hemodynamics, particularly during exercise. ß-Agonists, not anticholinergic drugs, are known to cause a significant drop in PaO2 after inhalation9 ,10 ,11 ,12 ,13 ,14 ,15 ,16 by the mechanism of a worsening ventilation/perfusion ratio.11 ,12 ,15 However, ß-agonists may have a more direct attenuating effects on the increase in pulmonary arterial pressure seen during exercise because they are more likely to be absorbed into pulmonary circulation than anticholinergic drugs, and they have a clear vasodilating effect on pulmonary circulation when systematically administered.17 ,18 Indeed, although there have been a few reports comparing the effect of the two classes of drugs on exercise performance and dyspnea,3 ,19 ,20 the results seem to be conflicting. We know of no studies comparing the effects of different classes of inhaled bronchodilators on pulmonary hemodynamics during exercise. In this study, we attempted to determine whether one type of drug, when given at the manufacturer's recommended dosage, is more effective than the other drug in attenuating the increase in right heart afterload at rest or during exercise in patients with stable COPD.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Twenty consecutive male patients with COPD served as the subjects in this study. The diagnosis of COPD was made based on clinical history, physical findings, chest roentgenogram, and pulmonary function tests according to the standard of the American Thoracic Society.21 The patients with malignant neoplasms, obvious coronary artery disease, idiopathic cardiomyopathy, or other heart diseases were excluded. Informed consent was obtained from all of the study patients after they had been given written information about the purpose of this study. The protocol was approved by the ethics committee of the Hokkaido University School of Medicine. The patients were all in clinically stable condition.

The patients were randomly separated into two groups. Eleven patients (the oxitropium group) were given oxitropium bromide, an anticholinergic drug. The other nine patients (the fenoterol group) were given fenoterol hydrobromide, a ß-agonist. The characteristics of these patients are shown in Table 1 . Although the patients in the fenoterol group who participated in the exercise study were older, on average, by 7 years than the patients in the oxitropium group, there were no significant differences between the two groups in any pulmonary function tests.


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  		Table 1. Characteristics of Subjects*

 
Experimental Setup
All of the patients underwent right heart catheterization. A catheter (Swan-Ganz model 93A-431H-7.5F; Baxter Healthcare Corp; Irvine, CA) was inserted through the right basilic vein or the right subclavian vein under local anesthesia, and was advanced to the pulmonary wedge position of the right descending pulmonary artery while being guided by pressure tracing and fluoroscopy. The right atrial pressure (RAP), the pulmonary arterial pressure (PAP), and the pulmonary capillary wedge pressure (PCWP) were monitored by transducers (model P10EZ; Becton Dickinson; Franklin Lakes, NJ), and were recorded on a polygraph system (model RM6000; Nihon Koden; Tokyo, Japan) along with an ECG for the measurement of the heart rate (HR). The external zero reference was positioned at the mid-chest level. For the mean measurements of RAP, PAP, and PCWP, the electrically averaged pressure was recorded over three consecutive respiratory cycles; the middle line between the peak and bottom of the record was then taken as representative because the electrically averaged pressure still showed a respiratory fluctuation. The cardiac output (CO) was measured using a computerized thermodilution technique (REF-1; Baxter Healthcare Corp) with an injection of 5 mL iced 5% glucose in water. The systemic blood pressure (SBP) was measured using a noninvasive BP monitoring system (model BP103M; Nihon Colin; Komaki, Japan) every 3 min.

With the patient under local anesthesia, a 20-gauge catheter (Terumo; Tokyo, Japan) was placed into the right radial artery for the sampling of arterial blood. Mixed venous blood samples, when necessary, were obtained from the pulmonary artery. The blood gas analysis was done immediately after sampling using a pH/blood gas analyzer (model ABL520; Radiometer Medical; Copenhagen, Denmark).

The patients had been instructed to refrain from drinking coffee, tea, or any caffeinated beverages, and from using any medications, including oral bronchodilators and vasodilators, for 16 h before the onset of the study. For those patients on long-term oxygen therapy, oxygen administration had been withdrawn at least 1 h before the study. During the experiment, the patients were placed in the supine position.

Experimental Protocol
Seven patients from each treatment group underwent stepwise incremental exercise twice using a cycle ergometer (model 881; Monark Exercise AB; Varberg, Sweden). An ergometer specially designed for the supine study was used as described in Figure 1 . The ergometer and bilateral grip handles were connected to the bed so that the position of the patient would remain stable during the exercise period. To secure the feet of the patient, the foot pedals of the device were equipped with straps. The patient was expected to pedal 50 cycle/min, and a metronome was used to pace the pedaling. The first exercise run began with a 12.5-W load for 3 min, followed by a 12.5-W incremental stepwise load increase every 3 min until the patient reached the limit of physical exertion and discontinued exercise. Thirty minutes after the first run, the patients inhaled either 2 puffs of oxitropium bromide (200 µg) or 2 puffs of fenoterol hydrobromide (400 µg) using a spacer. Thirty minutes after the inhalation, the patients underwent the second exercise run in a similar way until they reached the level they had achieved in the first run. All of the measurements were repeated at rest (the first control), at the end of the first run, 30 min after the first run (the second control), 30 min after the inhalation, and at the end of the second run (Fig 1 ).



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  		Figure 1. The position of the patients and the experimental protocol process are shown. The patients were placed in a supine position throughout the experiment. The first run was performed up to the patient's symptom limit, and the second run was done until the same workload was reached as in the first run. The hemodynamic and blood gas measurements were repeated at rest (the first control), at the end of the first run, at 30 min after the first run (the second control), at 30 min after the inhalation of the bronchodilator, and at the end of the second run, as shown by arrows.

 
Because they were unable to complete the exercise protocol due to severe dyspnea, lumbago, or leg pain, six patients (four from the oxitropium group and two from the fenoterol group) had their measurements taken at rest; the first measurement was taken before the drug was administered, and the second was taken 30 min after inhalation.

Bronchodilating Effect
To evaluate the bronchodilating effect of each inhaled drug, spirometry was performed using an autospirometer (model AS-4500; Minato Ikagaku; Osaka, Japan) on separate days within 1 week after the catheterization study was conducted. The FEV1 was measured before, 30 min after, and 60 min after bronchodilator inhalation. The test performance and the data selection followed the standards of the American Thoracic Society statement.22

Calculations
The hemodynamic parameters were calculated as follows: CI (L/min/m2) = CO (L/min)/body surface area (m2) PVR (dyne · s · cm-5 · m2) = 80 x (mean PAP - mean PCWP)/CI Double product = HR (BPM) x systolic SBP (mm Hg) CaO2(vol %) = 1.34 x Hb (g/dL) x SaO2 (%)/100 + 0.0031 x PaO2 (mm Hg) Oxygen delivery (mL/min/m2) = 1,000 x CI x CaO2/100

where CI is cardiac index, PVR is pulmonary vascular resistance, BPM is beats per minute, Hb is hemoglobin, and CaO2 is arterial oxygen content.

Data Analysis
All the data are shown as means (± SD). The comparison of the hemodynamic and blood gas data before and after bronchodilator inhalation was done using a paired t test. The comparison between the two groups was performed using an unpaired t test. The analysis of the FEV1 was made using an analysis of variance for repeated measurements, and a paired t test when appropriate. Values of p < 0.05 were accepted as statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Bronchodilating Effects
Both classes of drugs significantly improved the FEV1 at 30 and 60 min after inhalation when compared to the baseline. The FEV1 results for the oxitropium group at 30 and 60 min were, respectively, 0.99 ± 0.40 and 1.01 ± 0.38 L, compared to 91 ± 0.33 L at the baseline. The FEV1 results for the fenoterol group at 30 and 60 min were, respectively, 1.21 ± 0.39 and 1.22 ± 0.39, compared to 1.05 ± 0.41 at the baseline. There was no significant difference in the FEV1 between 30 and 60 min after inhalation in each treatment group. The improvement in the FEV1 with inhalation was not significantly different between the two groups.

Pulmonary and Systemic Hemodynamics
At Rest: Inhaled oxitropium slightly but significantly decreased HR and oxygen delivery, with no appreciable changes in SBP, PAP, CI, PVR, or PaO2. On the other hand, fenoterol significantly increased HR, CI, mixed venous oxygen tension (PvO2), and oxygen delivery, and significantly decreased PVR, PaO2, and PaCO2 (Table 2 ). In particular, the PaO2 significantly decreased by 5 mm Hg with fenoterol despite the hyperventilation observed in this case. The double product did not change with either drug.


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  		Table 2. Hemodynamic and Blood Gas Data at Rest Before and After Inhaled Bronchodilators*

 
During Exercise: There was no significant difference in the peak workloads achieved by the oxitropium and fenoterol groups, respectively: 25 ± 7 vs 29 ± 9 W. For the patients who completed the exercise procedure, most of the hemodynamic and blood gas data recovered to the baseline level (the first control) at the second control. Although there were small but significant differences in HR and PaCO2 between the first control and the second control (HR, 68 vs 72 BPM; PaCO2, 41.2 vs 39.8 mm Hg [p < 0.05 for each]), such a small difference was considered to have no significant influence on the data obtained subsequently. Both classes of drugs significantly attenuated exercise-induced increases in PAP and RAP (Table 3 ). The marked increase in PCWP seen during exercise was also attenuated by both classes of inhaled bronchodilators, although the change was statistically significant only in the case of oxitropium (p = 0.07). The magnitude of attenuation in the mean PAP ({Delta}PAP) caused by the inhaled bronchodilator at the maximal level of exercise was not significantly different between the oxitropium and fenoterol groups, respectively: 3 ± 2 vs 5 ± 4 mm Hg. The mean PAP was parallel with the mean PCWP or RAP in both treatment groups (Fig 2 ). At the peak workloads, the PaCO2 was significantly lower with either class of inhaled bronchodilator when compared to the value obtained in the control exercise run; however, no significant improvement or worsening was seen in the PaO2 with either class of bronchodilator. There was no change in HR, SBP, CI, PVR, or double products.


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  		Table 3. Hemodynamic and Blood Gas Data in Patients Undergoing Exercise Before and After Inhalation of Bronchodilators*

 


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  		Figure 2. The mean PAP (open circles), the mean PCWP (closed circles), and the mean RAP (open squares) at the peak level of exercise before and 30 min after the patients inhaled 2 puffs of oxitropium (n = 7) and 2 puffs of fenoterol (n = 7). The mean PAP decreased in parallel with the mean PCWP and the mean RAP after inhaled bronchodilators during exercise. The data show a mean (± SD). * = p < 0.05, {dagger} = p = 0.06 vs before inhalation.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The main findings in this study are that despite similar improvements in spirometric data with the two classes of inhaled bronchodilators, the ß-agonist (fenoterol), not the anticholinergic drug (oxitropium), caused significant increases in HR and CO, a decrease in PVR, and the deterioration of PaO2 at rest. However, these differences between the two drugs were not observed during exercise so that they were similarly beneficial in attenuating exercise-induced elevations in the means of PAP, PCWP, and RAP. Furthermore, the adverse effect of fenoterol on gas exchange that was seen at rest (the fall in PaO2 after inhalation) did not occur during exercise. The double product was not changed by bronchodilator inhalation at rest and during exercise. These data indicated that the two classes of inhaled bronchodilators were equally beneficial in attenuating right heart afterloads during exercise in patients with COPD.

Although there have been numerous studies comparing inhaled ß-agonists and anticholinergic drugs in patients with COPD, most of them have focused on the improvement of spirometric data (usually as FEV1). However, it is not clear that pulmonary function tests parallel symptomatic improvement and/or exercise performance. There have only been a few studies that examined the effects of two classes of inhaled bronchodilators on dyspnea and exercise ability.3 ,19 ,20 The results of these studies seem to be conflicting. In a recent report19 that found no significant measurable differences in exercise ability or exertional dyspnea in subjects with severe stable COPD inhaling standard doses of either a ß-agonist (albuterol) or an anticholinergic drug (ipratropium) for 1 week,19 the authors claimed that until further studies with more subjects could show a clinically meaningful superiority (if any) of one of the drugs, the patient response to bronchodilator therapy in severe COPD should be determined by the subjective benefit rather than by objective measures.

Concerning cardiovascular effects, the observed differences between the two classes of inhaled medications at rest seemed to agree with past reports. A number of studies23 ,24 ,25 similarly demonstrated that ß-agonists increased HR and CO, whereas anticholinergic drugs did not.23 ,24 ,25 ,26 In addition, the results of previous studies,9 ,10 ,11 ,12 ,13 ,14 ,15 ,16 as well as our study, demonstrated that an inhaled ß-agonist, but not an anticholinergic drug, caused a significant drop in PaO2 after inhalation. It is also known that when ß-agonists are systematically administered there is a clear vasodilating effect on pulmonary circulation in patients with COPD.18 ,27 Despite such potential differences between the two classes of drugs, we found no significant differences with respect to the effects on PAP, PCWP, and RAP during exercise. It is noteworthy that the adverse effect on gas exchange of the ß-agonist was also canceled during exercise in this study, indicating that improvement of the ventilation/perfusion ratio occurred during exercise.

The mechanisms by which the two classes of inhaled bronchodilators attenuated the exercise-induced increase in PAP might not be due to direct action of the drugs, but rather to an indirect effect that is a consequence of improved pulmonary mechanics. In patients with COPD, exercise is known to cause dynamic pulmonary hyperinflation.28 ,29 ,30 ,31 Trapped gas in the peripheral airways as a result of internal end-expiratory positive airway pressure32 may well lead to increases in PCWP, RAP, and PAP during exercise, even if the subjects do not have heart failure.33 In this study, the bronchodilator-induced attenuation in the PAP level paralleled that seen in the PCWP and RAP levels (Fig 2 ) without any significant changes in HR, SBP, CO, PVR, double product, and PaO2 between the control study and the bronchodilator study. In addition, as shown in Figure 3 , the {Delta}PAP obtained with either the ß-agonist or the anticholinergic drug at the maximal level of exercise had a significant correlation with the change in the mean PCWP. These findings may suggest that the observed attenuating effect of either class of inhaled bronchodilator on the exercise-induced increase in PAP was due to the improvement of pulmonary mechanics leading to a fall of intrathoracic pressure associated with bronchodilation followed by a fall of PCWP. In fact, a recent study by Belman et al34 demonstrated that the administration of an inhaled bronchodilator reduced intrathoracic pressure and dynamic pulmonary hyperinflation induced by exercise.



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  		Figure 3. The correlation between the {Delta}PAP and the change in the mean PCWP at the peak level of exercise in 14 patients who took inhaled bronchodilators and exercised. Both bronchodilators similarly attenuated increased PAP and PCWP during exercise.

 
In this study, we chose to use commercially recommended doses for both drugs because we believe that these are the doses prescribed by most practitioners. However, because it was shown that the effect of the inhaled anticholinergic drug was dose-dependent in terms of improvement of spirometric data35 ,36 and exercise performance,37 we may have underestimated the effect of oxitropium on pulmonary hemodynamics.

Another drawback in this study is that we had to examine the effect of each drug in different groups of patients because it was ethically hard to repeat cardiac catheterization for the same patient.

In summary, this study demonstrated that despite the potential differences between the effects of two classes of inhaled bronchodilators on pulmonary hemodynamics, there were no significant differences with regard to the attenuating effects on exercise-induced increases in right heart afterload. In other words, the two classes of inhaled bronchodilators are equally beneficial for pulmonary hemodynamics during exercise. This should be kept in mind when one considers the choice of drugs for patients with stable COPD.


   Footnotes
 
Correspondence to: Shunichi Saito, MD, First Department of Medicine, School of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo 060-8638, Japan

Abbreviations: BPM = beats per minute; CI = cardiac index; CO = cardiac output; HR = heart rate; PAP = pulmonary arterial pressure; {Delta}PAP = change in mean pulmonary arterial pressure; PCWP = pulmonary capillary wedge pressure; PvO2 = mixed venous oxygen tension; PVR = pulmonary vascular resistance; RAP = right atrial pressure; SBP = systemic blood pressure

Received for publication May 12, 1998. Accepted for publication August 25, 1998.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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