Mechanisms of Exertional Dyspnea in Fibrotic Interstitial Lung Disease
Condition: Lung; Disease, Interstitial, With Fibrosis
MeSH terms: Lung Diseases; Dyspnea; Lung Diseases, Interstitial
Study type: Interventional

Summary: 
      Exertional dyspnea is a major source of crippling distress and is the hallmark symptom of
      fibrotic interstitial lung disease (ILD). Due to the scientific community's poor
      understanding of the pathophysiological mechanisms of dyspnea there are no therapeutic
      interventions that consistently reduce dyspnea in this population. The investigators aim to
      determine the physiological mechanisms of exertional dyspnea in patients with fibrotic ILD
      and the impact of hyperoxia on exertional dyspnea and exercise endurance. This study will
      likely identify an important physiological mechanism of dyspnea in fibrotic ILD and may
      contribute to the development of effective therapies to reduce dyspnea in this population.

      The central hypothesis is that dyspnea in fibrotic ILD is primarily a result of an imbalance
      between the drive to breathe and the tidal volume response of the respiratory system (i.e.,
      neuromechanical uncoupling) and that experimental reduction of neuromechanical uncoupling via
      hyperoxic breathing will reduce exertional dyspnea and improve exercise endurance.
    

Detailed description: 
      The purpose of this study is to determine the physiological mechanisms of shortness of breath
      (dyspnea) in patients with fibrotic Interstitial Lung Disease (ILD) and to determine how
      breathing supplemental oxygen can manipulate these mechanisms to improve dyspnea and exercise
      capacity.

      The research question is twofold: (Aim 1) To determine the physiological mechanisms of
      exertional dyspnea in patients with fibrotic ILD; (Aim 2) To determine the effects of
      hyperoxia on exertional dyspnea and exercise endurance in patients with fibrotic ILD.

      Experimental Overview: Participants with fibrotic ILD and control participants will report to
      the exercise laboratory on four separate occasions separated by a minimum of 48 hours between
      visits. On visit 1, participants and control participants will complete medical history
      screening, chronic activity-related dyspnea questionnaires, anthropometric measurements,
      pulmonary function assessment, and a symptom limited incremental cycle exercise test for
      familiarization purposes. On visit 2, participants and control participants will perform
      pulmonary function testing followed by another incremental cycle exercise test. Detailed
      physiological and sensory measurements will be obtained on both visits but the primary
      analysis will be based on visit 2 results. Data from visit 2 will address the Aim 1. Visits 3
      and 4 will include pulmonary function testing followed by a constant-load cycle exercise test
      at 75% of peak incremental work rate while breathing, in randomized order, either room air or
      hyperoxia (60% oxygen). Participants and control participants breathing hyperoxia on visit 3
      will breathe room air on visit 4 and vice versa while being blinded to the gas concentration.
      A multi-pair electrode catheter that combines two balloons will be inserted into the
      esophagus and near infrared spectroscopy will be used to measure tissue oxygenation on visits
      2, 3 and 4. Data from visits 3 and 4 will address Aim 2.

      Measurements:

        -  Pulmonary Function: simple spirometry, plethysmography, diffusing capacity, maximum
           respiratory pressures, static compliance and recoil pressure will be performed on visit
           1. Pulmonary function testing on visits 2-4 will only include spirometry and
           plethysmography so that total lung capacity and vital capacity can be obtained for the
           determination of operating lung volumes.

        -  Dyspnea Evaluation: Dyspnea intensity 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. Upon exercise cessation, subjects 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,
           including minute ventilation, oxygen consumption (VO2), carbon dioxide production,
           partial pressure of end-tidal carbon dioxide, tidal volume (VT), and breathing
           frequency.

        -  Operating volumes will be derived from dynamic inspiratory capacity (IC) manoeuvres.
           Arterial oxygen saturation will be measured using pulse oximetry. Electrocardiography
           and blood pressure will be monitored for safety purposes.

        -  Respiratory Mechanics: Diaphragmatic electromyography (EMGdi) will be measured using a
           multi-pair electrode catheter that combines two balloons for measuring esophageal and
           gastric pressures. 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 calculated as the area within ensemble
           averaged esophageal pressure-volume loops.

      Statistical Analysis:

      Aim 1: Exercise-response slopes (e.g., Borg/VO2) will be determined. Briefly, the
      investigators will obtain the slope from a plot of Borg vs. VO2 for each participant's and
      control participant's incremental exercise test performed on visit 2. The investigators will
      determine the bivariate association of Borg/VO2 slope with VO2 slopes of neuromechanical
      uncoupling, drive to breathe, and VT response using Spearman correlation coefficients. The
      investigators will then force all three predictor variables into a multivariate linear
      regression model with Borg/VO2 slope as the outcome variable in order to identify the
      independent association of neuromechanical uncoupling with exertional dyspnea. Variables will
      be transformed to approximate a normal distribution if necessary and predictor variables
      reaching statistical significance will be assessed for a linear relationship with the outcome
      variable.

      Aim 2: The investigators will first use a paired t-test to identify changes in dyspnea and
      exercise time comparing room air breathing to hyperoxia during constant-load exercise tests
      on visits 3 and 4. Multivariate models will then be developed using the between-test
      difference in Borg dyspnea scale and exercise time for each individual as the outcome
      variables. Predictor variables will include the between-test difference in neuromechanical
      uncoupling and its individual components. Outcome and predictor variables for the dyspnea
      outcome will be based on the between-test difference of these variables at iso-time (i.e.,
      the maximum time for which the patient exercised for both the room air and hyperoxia tests).
      Predictor variables for exercise time will be measured at the end of the test.

      As exploratory analyses, the investigators will repeat the above multivariate linear
      regression analyses in the IPF subgroup, and the investigators will add a categorical ILD
      subgroup variable to these analyses in order to identify other inter-group differences.
      Additional adjustment for potential confounders (e.g., sex, body mass index, high resolution
      computed tomography fibrosis score) will be used in these exploratory analyses if the
      subgroup sample size is sufficient. A p value < 0.05 will be considered significant for all
      analyses. Data analysis will be performed using Stata v11.2 (StataCorp, Texas, USA).
    

Intervention name(s): Room air; Hyperoxia
Intervention type(s): Other; Other
Intervention description(s): Humidified room air (21% oxygen) will be inspired; 60% oxygen will be inspired
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Supportive Care
Keywords: dyspnea, exercise endurance, lung disease