Does Pulmonary Rehabilitation Improve Breathing of COPD Patients
Does Pulmonary Rehabilitation Improve Breathing of COPD Patients
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death world-wide.
 Dyspnea (i.e., sensations of breathlessness) is the hallmark symptom of patients with this
 disease. Pulmonary rehabilitation programs that incorporate exercise training remain the most
 effective non-pharmacological method of reducing dyspnea in COPD, however it is not
 understood how exercise training relieves dyspnea. Accordingly, the purpose of this study is
 to determine if pulmonary rehabilitation can reduce the disparity between the drive to
 breathe and the breathing response in patients with COPD and to determine if this reduction
 is associated with improvements in dyspnea during exercise.

 The investigators hypothesise pulmonary rehabilitation will reduce dyspnea at a standardized
 work rate and this reduction will be directly related to an improvement in the breathing
 response.
The purpose of this study is to determine if 8 weeks of pulmonary rehabilitation can reduce
 neuromechanical uncoupling (a disparity between the effort/drive to breathe and the breathing
 response) in patients with COPD and to determine if this reduction is associated with
 improvements in both the intensity and qualitative dimensions of dyspnea during exercise.

 Pulmonary rehabilitation is an exercise and education intervention designed to help patients
 cope with their dyspnea, and exercise effectively. Pulmonary rehabilitation programs that
 incorporate exercise training are the most effective non-pharmacological method of reducing
 dyspnea in COPD. However, the precise mechanisms of dyspnea relief following exercise
 training are still unknown. Understanding the pathophysiologcal underpinnings of this
 debilitating symptom is critical in order to develop effective symptom-based strategies for
 dyspnea management.

 Participants with COPD will report to the exercise laboratory on 3 separate visits. Visit 1
 will serve as an initial screening visit whereby participants will provide written informed
 consent prior to familiarization of all testing procedures and symptom scales followed by
 completion of an incremental cycle exercise test. The remaining 2 experimental visits will be
 conducted immediately before and after 8 weeks of pulmonary rehabilitation. Visits 2 and 3
 will include: symptom-related questionnaires, pulmonary function tests, functional ability
 test and a constant-work rate (CWR) cycle exercise test at 75% of the maximal work rate
 achieved during visit 1. The CWR cycle exercise tests will be performed with the
 instrumentation of an esophageal catheter and detailed physiological and sensory measurements
 will be obtained on both visits. The comparison of data from visits 2 and 3 will address the
 investigators' hypotheses.

 Study Participants: The study will include 12 COPD participants in total. Pulmonary
 Rehabilitation: The pulmonary rehabilitation program provides education and exercise training
 for patients with chronic lung disease to assist them with symptom management and improve
 their daily ability to function. The 8 week program involves 3 visits per week for 2 hours
 each visit (1 hour education and 1 hour exercise training). The pulmonary rehabilitation
 program is usual care for all participants in this study.

 Exercise Protocol: A symptom-limited incremental exercise test will be performed on visit 1
 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 10 watt
 stepwise increases in work rate every minute until symptom-limitation. The CWR test performed
 on visits 2 and 3 will consist of a 1 minute warm-up followed by an increase in work rate to
 75% of the maximum incremental work rate.

 Measurements Pulmonary Function: Spirometry, plethysmography, diffusing capacity, and maximum
 respiratory pressures will be performed on visit 1 according to standard recommendation.
 Visits 2 and 3 will include spirometry, plethysmography, and maximum respiratory pressures. 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. Pre- to
 post-intervention changes in dyspnea will also be assessed with the Transition Dyspnea Index.

 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, (tidal volume) 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 26. 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. Exercise tests will be terminated based on established criteria as per American
 College of Sports Medicine guidelines.

 Respiratory Mechanics: Diaphragmatic electromyography (EMGdi) will be measured using a
 multi-pair electrode catheter that combines two balloons for measuring esophageal and gastric
 pressures. Lidocaine spray or gel (a local anaesthetic) will be used to freeze the
 participant's nose and back of their throat. After which, while the participant sips water
 through a straw, an experienced technician will insert the catheter through the participants
 nose and into their stomach via their esophagus. The catheter will be positioned based on the
 strength of EMGdi signal during spontaneous breathing. The raw EMGdi signal will be converted
 to a root mean square (RMS). The maximum RMS for each inspiration will be determined between
 QRS complexes to avoid the influence of ECG artefact 30. Maximal EMGdi (EMGdimax) will be
 obtained during IC, sniff and maximal inspiratory pressure manoeuvres. The ratio of EMGdi to
 EMGdimax will be used as an index of neural respiratory drive. The ratio between VT and vital
 capacity (VC) will be used to represent the mechanical response of the respiratory system.
 Normalizing for EMGdimax and VC allows the stimulus intensity to be standardized and compared
 across individuals. Thus neuromechanical uncoupling of the respiratory system will be
 determined as the ratio (or interaction) between neural drive and the mechanical response of
 the respiratory system (EMGdi/EMGdimax : VT/VC).

 The mechanical work of breathing (WOB) will be determined using modified Campbell diagrams as
 used previously. Chest wall compliance will be obtained from the literature and positioned as
 previously described. The WOB will be partitioned into its resistive and elastic components.
 This data will be compared to the WOB data in previous COPD studies.

 Muscle oxygenation and hemodynamics: Muscle oxygenation will be noninvasively monitored using
 near infrared spectroscopy. 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 as limited data exists on the muscle
 oxygenation of the legs (vastus lateralis) and respiratory muscles (sternocleidomastoid,
 parasternal, and intercostals) in COPD patients.

 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 ± SD unless otherwise specified. Pre
 and post-pulmonary rehabilitation descriptive characteristics, exercise responses, and Borg
 ratings at standardized evaluation points (10 watt increments, VT/V'E inflection, and peak)
 will be compared using paired t-tests with Bonferroni corrections where appropriate. Pearson
 correlation coefficients will be used to examine the association between measured variables:
 neuromechanical uncoupling, 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 pre and post pulmonary
 rehabilitation using the McNemar's exact test at standardized 10 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).
Inclusion Criteria:

 -  A physician diagnosis of moderate-to-severe COPD

 -  Stable clinical COPD status (no history of an acute exacerbation requiring antibiotics
 or prednisone in the past 4 weeks)

 -  Post-bronchodilator Forced Expiratory Volume in 1 second (FEV1.0) ≥ 30 - < 80%
 predicted and FEV1.0/Forced Vital Capacity ratio < 0.7

 -  Body mass index > 18 or < 35 kg/m2

 -  Able to read and understand English

 Exclusion Criteria:

 -  Concurrent participation in or recent completion (<6 weeks) of pulmonary
 rehabilitation

 -  An ulcer or tumor in their esophagus, or a nasal septum deviation (as reported by the
 participant)

 -  Had recent nasopharyngeal surgery

 -  Have a cardiac pacemaker

 -  Allergies to latex and sensitivities to local anesthetics

 -  Uncontrolled hypertension

 -  Diagnosis of diabetes

 -  Previous physician diagnosis of cardiovascular disease including: angina, acute
 coronary syndrome, heart failure, cerebrovascular disease, thromboembolic disease,
 peripheral vascular disease

 -  Other chronic lung disease including: asthma, interstitial lung disease, or pulmonary
 hypertension

 -  Chronic hepatic disease, chronic renal disease, or other systemic inflammatory disease

 -  Use of chronic oral steroids

 -  Dementia or uncontrolled psychiatric illness

 -  A disease other than COPD that could contribute to dyspnea or exercise limitation

 -  Contraindications to clinical exercise testing