Cardiac Limitations in Chronic Obstructive Pulmonary Disease: Benefits of Bronchodilation
Condition: Chronic Obstructive Pulmonary Disease; COPD
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Study type: Interventional
Phase: Phase 4

Summary: 
      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).
    

Detailed description: 
      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.
    

Intervention name(s): Tiotropium; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Participants received once daily Spiriva capsules for oral inhalation: 18 mcg tiotropium powder, for use with HandiHaler device.; Participants randomized to this arm received a once daily oral inhalation of placebo powder to match the standard active comparator dose, using the HandiHaler device.
Other intervention name(s): Spiriva
Intervention MeSH terms: Tiotropium Bromide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: COPD; Tiotropium; Spiriva