Chronic Obstructive Pulmonary Disease Clinical Trial
Official title:
Cardiac Limitations in Chronic Obstructive Pulmonary Disease: Benefits of Bronchodilation
This study is being done to examine the influence of Tiotropium (good or bad) on heart function at rest and during exercise in patients with moderate to severe chronic obstructive pulmonary disease (COPD).
Patients who develop chronic obstructive pulmonary disease (COPD) have a loss of elastic
recoil of the lungs, have remodeling in the airways and pulmonary vasculature, develop
inhomogeneities in ventilation (VA) and perfusion (Qc) and gradually lose their reserves for
producing expiratory flow, particularly over the mid to lower lung volumes. As a result,
they develop air trapping, have slowed expiration, and gradually hyperinflate with a large
residual volume, an exaggerated total lung capacity, reduced vital capacity, and markedly
reduced maximal expiratory flows. With exercise, patients with moderate to severe COPD are
further challenged by the need for increased ventilation. Expiring against the narrowed
airways results in breathing at higher and higher lung volumes until the elastic load on
inspiration increases the work and cost of breathing to the point where exercise
discontinues. It remains controversial if this scenario leads to primarily dyspnea from the
weak and heavily recruited inspiratory muscles, inspiratory muscle fatigue or if a primary
limitation might be related to the relatively large cardiac output required for the
respiratory muscles, at the expense of the locomotor muscles, resulting in leg fatigue. The
expiratory load also increases intrathoracic pressure and reduces the gradient for venous
return, thus having the potential to reduce cardiac output. Pulmonary hypertension develops
and may influence blood flow to the left side of the heart further inhibiting cardiac
output. The ineffective inspiratory pressure generation by the diaphragm may also reduce the
typical benefits of the respiratory muscle pump on venous return and the marked
hyperinflation may influence left ventricular filling due to competition for intrathoracic
space. Thus, although COPD primarily influences the respiratory system, we believe it has
profound effects on cardiac function, and during exercise this may play a particular
limitation. Use of a long-acting anticholinergic agent such as Tiotropium partially reverses
airway obstruction (expiratory load) and hyperinflation, both potentially improving
cardiovascular function. The focus of this research will be to determine influence of
Tiotropium on cardiac parameters measured both at rest and during exercise.
The focus of this study was to determine the influence of Tiotropium (Spiriva) on cardiac
parameters measured both at rest and during exercise. More specifically, we first examined
cardiac function in a group of COPD patients and healthy age and gender matched controls.
Our hypothesis was that at rest cardiac function would be similar between groups; however,
with light and heavier exercise, there would be evidence for a blunted stroke volume and
perhaps cardiac output in the COPD patients. Second, we compared in a placebo-controlled
double blinded manner cardiac function with and without chronic use of tiotropium in age,
gender, and disease matched COPD patients. Our hypothesis was that in the Tiotropium
(Spiriva) group at a matched workload, the reduced obstruction would allow for improved
cardiac function, specifically an increase in stroke volume and reduction in heart rate. The
interactions in this population between metabolic demand, fitness, lung mechanics, and
cardiovascular function are complicated and thus studies were pursued at matched workloads
and heart rate as well as with heavier exercise in an attempt to discriminate a primary
influence of altered obstruction on cardiovascular function.
The participants will be asked to come to the Cardiopulmonary Research Laboratory on 4
occasions (separate visits) for exercise testing (typically over the course of 2 to 4
weeks). Each session will take approximately 1-4 hours to complete and in the COPD
population, visits will be repeated after receiving placebo or Tiotropium for 4 weeks.
All of the exercise testing will be performed on an exercise bicycle either in the upright
or semi-supine (recumbent) position and the participant will wear a SCUBA-type mouthpiece
and a nose clip to analyze expired air. In addition, an EKG will be used to monitor heart
rate and rhythm.
Visit 1 (Screening Visit): During the first visit, participants will have a brief exam by a
pulmonary physician. The exam will include a complete blood count (CBC) to rule out anemia,
baseline spirometry to assess lung volumes and flow rates to meet entry criteria, and in
women of childbearing potential a pregnancy test. They will also be taken off theophylline
and inhaled anticholinergics, but allowed to continue long acting inhaled beta agonists
(LABA) or short acting beta agonist (SABA) for a rescue medication. Subjects on long acting
inhaled beta agonists will be asked to discontinue this medication temporarily, 48 hr. prior
to each study visit, but restarted upon completion of the visit.
Visit 2: A minimum of 48 hours after the first visit, participants will return for complete
measures of lung volumes, flow rates, and diffusing capacity of the lung for carbon monoxide
(DLCO), a baseline echocardiogram and a maximal exercise test on a cycle ergometer. Before
the exercise begins, participants will have one or two small balloon(s) (2 inches long,
deflated) attached to a small plastic tube (the width of a pencil tip) inserted through the
nasal cavity and into the esophagus. This is done to measure respiratory muscle work.
Participants will receive a numbing gel (2% lidocaine) to numb the nasal passage and upper
esophagus prior to insertion of the balloon(s). During the insertion of the esophageal
balloons, participants will also be asked to swallow water to minimize gagging and assure
correct balloon placement in the esophagus. Participants will also be asked to breathe a
mixture of gases containing acetylene (0.6%), dimethyl ether (1.8%), oxygen (21%, same as
room air), helium (9%) and nitrogen (69.4%). The mixture of gases will be inhaled at various
time points over the course of the exercise session for 8 to 10 breaths at a time. This is
done to non-invasively measure cardiac output.
Visit 3: Visit 3 will involve steady-state semi-recumbent cycling exercise at two
steady-state exercise intensities; 40 percent of peak work and (after a brief rest) an
intensity eliciting a heart rate of 110 beats per minute (to standardize diastolic
duration). Before the exercise begins, participants will have one or two small balloon(s) (2
inches long, deflated) attached to a small plastic tube (the width of a pencil tip) inserted
through the nasal cavity and into the esophagus. This is done to measure respiratory muscles
at work. Participants will receive a numbing gel (2% lidocaine) to numb the nasal passage
and upper esophagus prior to insertion of the balloon(s). During the insertion of the
esophageal balloons, participants will also be asked to swallow water to minimize gagging
and assure correct balloon placement in the esophagus. Participants will also be asked to
breathe a mixture of gases containing acetylene (0.6%), dimethyl ether (1.8%), oxygen (21%,
same as room air), helium (9%) and nitrogen (69.4%). The mixture of gases will be inhaled at
various time points over the course of the exercise session for 8 to 10 breaths at a time.
This is done to non-invasively measure cardiac output. Also during the session, a
sonographer will use ultrasound to measure cardiac pressures and volumes.
Visit 4: Visit 4 will involve steady-state exercise at 70% of peak work. Before the exercise
begins, participants will have one or two small balloon(s) (2 inches long, deflated)
attached to a small plastic tube (the width of a pencil tip) inserted through the nasal
cavity and into the esophagus. This is done to measure respiratory muscles at work.
Participants will receive a numbing gel (2% lidocaine) to numb the nasal passage and upper
esophagus prior to insertion of the balloon(s). During the insertion of the esophageal
balloons, participants will also be asked to swallow water to minimize gagging and assure
correct balloon placement in the esophagus. Participants will also be asked to breathe a
mixture of gases containing acetylene (0.6%), dimethyl ether (1.8%)oxygen (21%, same as room
air), helium (9%) and nitrogen (69.4%). The mixture of gases will be inhaled at various time
points over the course of the exercise session for 8 to 10 breaths at a time. This is done
to non-invasively measure cardiac output.
Upon completion of these baseline visits, the COPD patients will be randomly assigned to a
standard dose of Tiotropium once-daily (18 µg) or placebo for 4 weeks (or until study
completion as visits 2-4 may require 1-2 wks to complete). Patients otherwise will receive
usual care, except (as noted) for discontinuing other anticholinergic bronchodilators and
theophylline. They will also discontinue long acting beta agonists for 48 hours prior to
performing each of the designated visits. At the end of this intervention period, the
procedures outlined in Visits 2-4 will be repeated (on the COPD patients only). All post
intervention visits will be timed so that the primary measures will be made 1.5 to 2 hrs
post dose of Tiotropium.
;
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
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