Effects of Inspiratory Muscle Training on Shortness of Breath (Dyspnea) and Postural Control in Patients With COPD
Effects of Inspiratory Muscle Training on Shortness of Breath (Dyspnea) and Postural Control in Patients With COPD
Shortness of breath (dyspnea) is an important symptom during physical exertion in patients
 with chronic obstructive pulmonary disease (COPD) and is related to respiratory muscle
 weakness. Dyspnea is a multidimensional sensation. The sensory perceptual domain (perceived
 dyspnea intensity) has been study extensively. The perception of respiratory distress
 (unpleasantness of dyspnea) has not received as much attention. Inspiratory muscle training
 (IMT) has been shown to improve inspiratory muscle function and reduce dyspnea intensity.
 Balance impairments increasing the risk of falling is another recognized problem in patients
 with COPD. Postural balance has been shown to be especially impaired in patients with COPD
 who have pronounced respiratory muscle weakness. Improvements in respiratory muscle function
 might improve balance control in patients. Respiratory Muscle Metaboreflex is known as
 respiratory muscle work during exercise reflexively induces sympathetically mediated
 vasoconstrictor activity, there by compromising blood flow and oxygen delivery to active limb
 and respiratory muscles.

 Eight weeks of controlled IMT is hypothesized to reduce both intensity as well as
 unpleasntness domain of dyspnea perception, improve postural control and improves blood flow
 and oxygen delivery to limb muscles in patients with COPD who have pronounced respiratory
 muscle weakness.
The purpose of this clinical trial is to elucidate mechanisms of dyspnea relief and
 improvements in postural control after inspiratory muscle training (IMT) in patients with
 COPD.

 An endurance cycle exercise test (Constant work rate (CWR) test) will be used to evaluate
 dyspnea intensity and unpleasantness at comparable breathing efforts, at comparable work
 rates on the cycle ergometer, before and after IMT. Patients will be performing a CWR test at
 75% of the peak work rate achieved during a maximal incremental cardiopulmonary exercise test
 (CPET). Before, during and after CWR cycling tests patients will rate their intensity of
 dyspnea, unpleasantness of dyspnea, breathing related-anxiety and leg discomfort using a
 modified 10- point Borg scale. Patients will be asked to report qualitative descriptors of
 dyspnea at the end of the CWR cycling test. Maximum duration of the CWR test will be recorded
 and levels of minute ventilation will be registered continuously throughout the exercise
 protocol. With this endurance exercise test the investigators will be able to assess changes
 in the onset of dyspnea (intensity and unpleasantness) and the performance in endurance
 exercise before and after IMT.

 Surface electromyography (EMG), and a multipair esophageal electrode catheter system will be
 used during CWR exercise to evaluate respiratory muscle recruitment, respiratory effort and
 neural drive to the different respiratory muscles. The catheter will be inserted to
 continuously record Pes (esophageal pressure), Pgas (gastric pressure) and EMGdi
 (electromyogram of the diaphragm muscle). PesMax (maximal esophageal pressure), PgasMax
 (maximal gastric pressure) and PdiMax (maximal transdiaphragmatic pressure) will be obtained
 during maximal sniff and cough maneuvers. Transcutaneous surface electromyography (sEMG)
 techniques will be applied to scalene, sternocleidomastoid and parasternal intercostal
 muscles to register neural drive to these respiratory muscles. With this measurements, the
 investigators will be able to assess whether there are any changes in respiratory muscle
 recruitment patterns and respiratory neural drive to the different respiratory muscles after
 IMT.

 During exercise 'Respiratory Muscle Metaboreflex' will lead to sympathetically mediated
 vasoconstriction of limb locomotor muscle, less blood and oxygen supply to active limbs
 muscle there by locomotor muscle fatigue occurred. Quadriceps twitch forces evoked by
 magnetic stimulation of femoral nerve will be assessed to measure locomotor muscle fatigue at
 identical exercise time points during CWR test before and after the intervention. With this
 technique, the investigators will be able to assess whether the onset of locomotor muscle
 fatigue is delayed after IMT.

 An isocapnic hyperpnea trial will be performed to assess respiratory muscle perfusion,
 dyspnea intensity and unpleasantness, respiratory muscle recruitment pattern, respiratory
 effort and neural respiratory drive without the work of locomotor muscle before and after
 IMT. Patients will be asked to maintain a targeted minute ventilation pattern equal to their
 breathing frequency, tidal volume and minute ventilation recorded at rest and during the
 final minute of constant load exercise test (at ~75% WRpeak). Experimenters will provide
 verbal guidance to patients to adjust the rate and depth of their breathing such that the
 target ventilation will be obtained and maintained constant within ±5%. Isocapnia will be
 maintained by having subjects inspire from a Douglas bag containing 5% CO2, 21% O2, balance
 N2 that will be connected to a two-way non-rebreathing valve (model 2700, Hans Rudolph) by a
 piece of tubing.

 Loaded breathing tests will be performed to assess dyspnea intensity and unpleasantness,
 respiratory muscle recruitment patterns, respiratory effort and neural respiratory drive.
 Patients will be asked to breathe through a tapered flow resistive loading (TFRL) device
 (powerbreathe KH1) as long as they can (3-7 minutes), the resistance will be set at 50% of
 patients' PImax. Heart rate, oxygen saturation, and number of breaths will be monitored.
 Before and after the test Borg dyspnea, inspiratory effort and unpleasantness will be
 recorded. The test will be repeated after 8 weeks of IMT, at the same resistance. Borg
 dyspnea, inspiratory effort and unpleasantness will be recorded at time limit of pre-training
 and at the symptom limit. The longest time for post training can be up to 15 minutes.

 Respiratory (i.e., intercostal, scalene and abdominal) and locomotor muscle blood flow index
 (i.e., vastus lateralis) will be simultaneously measured during isocapnic hyperpnea trials as
 well as during CWR test (at 75% of the peak work rate) before and after IMT according to a
 previously established method using Near-Infrared Spectroscopy (NIRS) and indocyanine green
 (ICG). Respiratory (i.e., intercostal, scalene, abdominal) and locomotor muscle (i.e., vastus
 lateralis) oxygen delivery will be calculated by multiplying blood flow index to arterial
 oxygen content, the latter will be calculated non-invasively by pulse oximetry. Respiratory
 (i.e., intercostal, scalene, abdominal) and locomotor muscle (i.e., vastus lateralis) oxygen
 saturation (Stio2) - an index of oxygen availability reflecting the balance between oxygen
 supply and demand-, will be recorded continuously during the trial by NIRS.

 A noninvasive technique for studying the neural processing of respiratory sensations will be
 used to assess changes in the affective unpleasantness component of dyspnea during a
 standardized loaded breathing task. Electroencephalography (EEG) will be used to measure
 respiratory related evoked potentials (RREPs) during loaded and unloaded breathing. The RREP
 recorded from EEG is a measurement of cerebral cortical activity, which is elicited by the
 activation of lung and muscle mechanoreceptors due to short inspiratory occlusions. Patients
 will be wearing EEG sensors [129 channel system, Electrical Geodesics Inc., Eugene, USA] and
 breathe through a breathing circuit with a non-rebreathing valve via a mouthpiece. The
 inspiration will be interrupted briefly for 150 milliseconds every two to six breaths by
 activation of the occlusion valve with pressurized air, which induces the RREP. Patients will
 be rating their perceived intensity and unpleasantness of dyspnea and intensity of occlusion
 on a Borg scale while inspiratory load and occlusion will be applied via a breathing valve.
 This method will be used to assess if there is less unpleasantness associated with a giving
 level of dyspnea elicited by a resistive breathing task and whether these changes are
 correlated with changes in the central processing of the dyspnea sensation.

 To evaluate postural balance, displacement of the center of pressure (CoP) in will be
 estimated from the raw force plate data using the equation: CoP = Mx/Fz (medio-lateral) and
 CoP=My/Fz (anterior-posterior). CoP will be measured during upright standing with and without
 vision, on stable and unstable (foam pad) support surface. During some conditions, local
 muscle vibration on ankle and/or back muscles will be applied to evaluate the role of
 proprioception in postural control. Furthermore, in some conditions a repetitive ballistic
 arm movement will be asked to evaluate the effect of a internal perturbation on postural
 control. Root mean square values of the CoP displacements will be used for the analysis of
 postural stability measures and mean values will be calculated for the vibration trials to
 analyze the expected directional effect. A ratio of the CoP displacements of the ankle
 muscles vibration trial regard to the back muscles vibration trial will be calculated to
 determine the proprioceptive postural control strategy.

 A sample size of 16 participants for intervention group and 8 for control group are required
 to detect a difference of one unit in dyspnea Borg-10 scale, assuming a SD of 1 unit in the
 change in dyspnea score between pre and post measurements (power 80%, level of significance
 p<0.05). These estimates are based on previous work on dyspnea during exercise. Therefore 24
 clinically stable COPD patients with inspiratory muscle weakness (PiMax<70% predicted or
 <60cmH2O) and dyspnea symptoms (BDI<7) will be included. Patients who are unable to perform
 exercise testing will be excluded.

 Patients will perform daily training consisting of two training sessions of 30 breaths
 (intensity ~50% of PiMax; 4-5 minutes per session). One session per week will be performed
 supervised at the research center. IMT will be performed using an electronic tapered flow
 resistive loading (TFRL) device [POWERbreath®KH1, HaB International Ltd., Southam, UK] for 8
 weeks. The PiMax will be measured every week in order to increase the appropriate training
 intensity to around 50% of the PiMax at that moment. The sham group will perform IMT at an
 inspiratory load that is not expected to improve inspiratory muscle function (intensity <10%
 of baseline PiMax; unchanged throughout the protocol).

 Differences in primary and secondary outcomes between groups after 8 weeks of IMT will be
 compared adjusting for baseline differences in an analysis of covariance (ANCOVA).
Inclusion Criteria:

 -  Clinical Diagnosis of COPD

 -  Inspiratory Muscle Weakness (Pi,max <70% predicted or < 60 cmH2O)

 -  Baseline dyspnea index (BDI) < 7

 -  Peripheral muscle fatigue present after CPET

 Exclusion Criteria:

 -  Major cardiovascular

 -  Limiting exercise capacity more than pulmonary function impairment

 -  Severe orthopedic with major impact on daily activities

 -  Psychiatric or cognitive disorders

 -  Progressive neurological or neuromuscular disorders

 -  Longterm O2 therapy

 -  Previous inclusion in rehabilitation program (<1 year)