Evaluating Sensations of Breathlessness in Patients With Cystic Fibrosis
Condition: Lung; Disease; Cystic Fibrosis; Healthy
MeSH terms: Cystic Fibrosis; Lung Diseases; Fibrosis
Study type: Observational

Summary: 
      Shortness of breath (dyspnea) during exercise is a major source of distress and is a commonly
      reported symptom in patients with cystic fibrosis (CF). Due to the investigators' poor
      understanding of how dyspnea develops, there are no treatments that consistently reduce
      dyspnea in this population. The investigators aim to acquire a more comprehensive
      understanding of the physiological mechanisms of exertional dyspnea in CF patients. This
      study will likely identify an important physiological mechanism of dyspnea in CF and may
      contribute to the development and use of effective treatments to reduce dyspnea in this
      population.

      The central hypothesis is that the impaired tidal volume (VT) response during exercise in CF,
      in the setting of increased ventilatory demand will give rise to different qualitative
      descriptions of exertional dyspnea compared with healthy age and sex-matched controls.
      Specifically, CF patients will select "increased work and effort" as their dominant
      descriptor of dyspnea up to the VT inflection/plateau. Beyond this point, CF patient's
      dominant descriptor will become "unsatisfied inspiration." In contrast, healthy control
      participants will report "increased work and effort" throughout all phases of exercise and
      will not report "unsatisfied inspiration", even after the VT inflection/plateau.
    

Detailed description: 
      The purpose of this study is to determine if sensations of breathlessness (dyspnea) are
      qualitatively and quantitatively different in patients with cystic fibrosis (CF) compared to
      age and sex-matched healthy controls during exercise, and to determine if these differences
      can be explained by differences in the ventilatory response to exercise.

      Understanding the progression of dyspnea during exercise will enable the investigators to
      better understand the pathophysiological mechanisms of this debilitating symptom in patients
      with CF. A more comprehensive understanding of the mechanisms underlying exertional dyspnea
      may ultimately lead to new therapeutic interventions (pharmacologic and non pharmacologic)
      that would positively impact exercise limitations in CF. A healthy control group will enable
      investigators to better identify the "normal" physiological and perceptual responses to
      exercise so that direct comparisons to patients with CF may be drawn.

      Experimental Overview: Participants with CF and healthy control participants will report to
      the exercise laboratory for one visit. Informed consent, medical history screening,
      evaluation of chronic activity-related dyspnea and anthropometric measurements will firstly
      be obtained. Subjects will then be familiarized with the cycle ergometer, breathing apparatus
      and symptom scales. This will be followed by simple spirometry testing. After which
      participants will rest prior to a symptom limited incremental cycle exercise test. Detailed
      physiological and sensory measurements will be obtained during the familiarization and
      exercise test sessions. Data from the exercise test will address our hypotheses.

      Study Participants: The study will include 40 participants in total. Of the 40 participants,
      20 will be patients with CF and 20 will be healthy age and sex-matched controls.

      Exercise Protocol: A symptom-limited incremental exercise test will be performed using an
      electronically braked cycle ergometer according to recommended guidelines. The test will
      consist of steady-state rest for 10 minutes, a 1 minute warm-up at 0 watts, and 20 watt
      stepwise increases in work rate every 2 minutes until symptom-limitation.

      Measurements Familiarization Session: Participants and control participants will exercise on
      the cycle ergometer at a very low work rate (0W and 20W) for 2 minutes at each intensity in
      order to become familiarized with the cycle ergometer, breathing apparatus and symptom scales
      (see details below).

      Pulmonary Function: Spirometry and maximum respiratory pressures, will be performed according
      to standard recommendations. A commercially available cardiopulmonary testing system (Vmax
      229d with Autobox 6,200 DL; SensorMedics, Yorba Linda, CA) will be used, and all measurements
      will be expressed as percent of predicted normal values.

      Dyspnea Evaluation: Dyspnea intensity (defined as "the sensation of laboured or difficult
      breathing") and perceived leg discomfort will be evaluated at rest, every minute during
      exercise, and at peak exercise using the modified 10-point Borg scale on all testing visits.
      Participants will be asked to describe their dyspnea during exercise prior to the intensity
      ratings and at end-exercise using the following 3 descriptors: (1) "my breathing requires
      more work and effort" (work and effort); (2) "I cannot get enough air in" (unsatisfied
      inspiration); (3) "I cannot get enough air out" (unsatisfied expiration). None to all 3 of
      the descriptors can be chosen at any one time. Upon exercise cessation, participants will be
      asked to verbalize their main reason(s) for stopping exercise (i.e., breathing discomfort,
      leg discomfort, combination of breathing and legs, or some other reason) and to select
      qualitative descriptors of breathlessness using an established questionnaire.

      Cardio-respiratory Responses to Exercise: Standard cardio-respiratory measures will be
      recorded on a breath-by-breath basis and averaged over 30-second epochs, including minute
      ventilation (V'E), oxygen consumption (VO2), carbon dioxide production (CO2), partial
      pressure of end-tidal CO2, VT, and breathing frequency (Vmax 229d with Autobox 6,200 DL;
      SensorMedics, Yorba Linda, CA). Operating volumes (i.e., end-expiratory and end-inspiratory
      lung volumes) will be derived from dynamic inspiratory capacity (IC) manoeuvres as previously
      described. An indirect measure of neural respiratory drive will be obtained non-invasively
      using bi-polar surface electromyography (EMG) electrodes placed over the right parasternal
      intercostals and sternocleidomastoid as previously described. For safety purposes,
      electrocardiography will be monitored using a 12-lead electrocardiogram (ECG), blood pressure
      will be measured using a manual sphygmomanometer, and arterial oxygen saturation will be
      monitored using pulse oximetry. All exercise tests will be administered by experienced
      exercise physiologists. Tests involving patients with CF and healthy controls will be
      supervised by a physician. Exercise tests will be terminated based on established criteria as
      per American College of Sports Medicine guidelines.

      Muscle oxygenation and hemodynamics: Muscle oxygenation will be noninvasively monitored using
      near infrared spectroscopy in all participants. A four-channel continuous-wave near-infrared
      spectroscope (Oxymon M III, Artinis Medical Systems, BV, The Netherlands) will be used to
      determine oxyhemoglobin, deoxyhemoglobin, and total hemoglobin by measuring light attenuation
      at 760 and 864 nm wavelengths, and analyzed using algorithms based on the modified
      Beer-Lambert law. This data will be used for descriptive exploratory purposes to examine the
      relationship between muscle oxygenation of the leg (vastus lateralis) and respiratory muscles
      (sternocleidomastoid, parasternal, and intercostals), and sensory responses to exercise in CF
      patients.

      Computed Tomography Phenotyping: Existing chest computed tomography (CT) scans, obtained
      through routine clinical practice, will be used for descriptive exploratory purposes to
      examine the relationship between the extent of bronchiectasis vs. mucus plugging vs. air
      trapping (based on CF-specific CT scoring) on the physiological and sensory responses to
      exercise in patients with CF.

      Inflection Point of the VT and V'E Relationship: VT data will be averaged over 30-second
      epochs and will be plotted against V'E at rest and throughout all exercise intensities for
      each individual participant. The point at which VT deviates from linearity and begins to
      plateau will be defined as the inflection point of the VT and V'E relationship. Two different
      observers will determine the inflection point for each participant during the incremental
      exercise test by examining individual Hey plots.

      Statistical Analysis Data will be presented as means ± standard deviation (SD) unless
      otherwise specified. Between group comparisons (CF vs. healthy control) for descriptive
      characteristics, exercise responses, and Borg ratings at standardized evaluation points (20
      watt increments, VT/minute ventilation (V'E) inflection, and peak) will be compared using
      unpaired t-tests with Bonferroni corrections where appropriate. Pearson correlation
      coefficients will be used to examine the association between measured variables: parasternals
      electromyography, breathing pattern, operational lung volumes, Borg ratings, and exercise
      variables. Reasons for stopping exercise and qualitative descriptors of dyspnea will be
      analyzed as frequency statistics and compared between control and CF participants using the
      Fisher's exact test at standardized 20 watt increments in work-rate, VT/V'E inflection, and
      peak exercise. A P-value less than 0.05 will be regarded as statistically significant.
      Statistical analysis of the data will be performed using Stata v11.2 (StataCorp, Texas, USA).

      Sample Size and Power Calculation: Determining adequate sample size for qualitative
      descriptors of dyspnea in CF is difficult because limited data exists in this population.
      Therefore, the sample size in the present study is based on previous studies of dyspnea
      intensity ratings and the VT response in patients with chronic obstructive pulmonary disease
      during exercise. In these studies, statistically significant results were detected using a
      sample size of 16, under the assumptions: a SD of approximately 1.5 units, a difference of
      approximately 1.5 units found between the VT/V'E inflection point and peak exercise, a
      two-sided test, 80% power, and α = 0.05. Thus a sample size of 20 participants in the present
      study will likely have adequate power for the investigators' analyses.
    

Observational model: Case-Control
Sampling method: Probability Sample
Study population: 
        The CF patients will be recruited from the St. Paul's Hospital Adult CF Clinic. Healthy
        control participants will be recruited from the Vancouver area.
      
Keywords: dyspnea; exercise; cystic fibrosis; neuromechanical dissociation