Impact of Muscle Afferent Feedback During Exercise in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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Recently, direct evidences point to the contributing role of peripheral muscle fatigue in exercise tolerance among patients with COPD. However, the physiological mechanisms by which peripheral muscle fatigue impairs exercise tolerance are still unknown, as factors regulating peripheral muscle fatigue in COPD may be complex. One possible link between limb muscle fatigue and exercise intolerance could be enhanced afferent signals from the active limb muscles to the central command, thereby limiting central motor output and eventually leading to exercise termination. A direct method to investigate the regulation of peripheral muscle fatigue during exercise in patients with COPD is the blockade of peripheral neural afferents via lumbar anesthesia. Consequently, investigating the interplay between the peripheral muscular component and the central motor command during self-paced exercise could shed light on the regulation of peripheral muscle fatigue in COPD and its implication in exercise intolerance.

Detailed Description
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The aim of the study is to characterize the role of peripheral muscle afferents on the development of muscle fatigue, cardiorespiratory response and exercise tolerance to constant-workrate endurance cycling exercise in patients with COPD. In a double-blind randomized design, patients with GOLD stage II-III COPD will be recruited and will complete a constant-workrate cycling test following either the injection of a placebo [NaCl, interspinous L2-L3] or an opioid [Fentanyl 25 µg, intrathecal L2-L3] inhibiting central feedback of peripheral muscles sensory afferents. Quadriceps force (TwQ) will be measured by magnetic stimulation of the femoral nerve and central chemoreceptors response will be assessed by CO2 rebreathing, both performed before and after the injection. Finally, TwQ will also be measured after the endurance cycling test to assess the magnitude of quadriceps fatigue induced by symptom-limited exercise.

Official Title
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Impact of Somatosensory Feedback on Peripheral Muscle Fatigue and Exercise Tolerance in Patients With COPD

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Fentanyl
* Drug: Placebo comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Smoking history > 15 pack-years COPD GOLD II-III (30 % predicted < FEV1 < 80 % predicted; FEV1/FVC < 0.70) Exclusion Criteria: Unstable condition Recent exacerbation (<3 months) Recent cancer (<3 months) Myopathy, neuromuscular disease Unstable cardiac disease Hepatic, kidney, intestinal disease BMI > 35 PaCO2 > 45 mmHg PaO2 < 60 mmHg

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fentanyl<br> | Drug: Fentanyl<br>* Single-dose of intrathecal fentanyl [25ug] Duration of fentanyl : 3.5 hours<br>|
| Experimental: Placebo<br> | Drug: Placebo comparator<br>* placebo [NaCl]<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endurance time | Exercise tolerance is referred as the endurance time (sec) during constant-workrate cycling test at 80 % of the predetermined maximal workload in every conditions (placebo and fentanyl) | 60-min post-anesthesia - From the start to the end of the constant-workload cycling test (limited by symptoms of the patients) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilatory response | The ventilatory response (Ventilation, L/min) will be monitored continuously during the cycling test and will be compared between the two conditions (placebo vs. fentanyl) | 60-min post-anesthesia-From the start to the end of the constant-workload cycling test (limited by symptoms of the patients) | 
| Quadriceps muscle fatigue | The quadriceps muscle fatigue will be monitored before and after the cycling test to quantify the extent of muscle fatigue produced by the cycling test. This will be done by magnetic stimulation of the femoral nerve and maximal voluntary contraction. Also, non-invasive surface electromyography (EMG) of the quadriceps will help to better characterize muscle fatigue. | 15-min after the end of constant-workload cycling test | 
| Dynamic hyperinflation | Dynamic hyperinflation will be monitored periodically every 2-min during the cycling test by manoeuvres of inspiratory capacity and will be compared between the two conditions (placebo vs. fentanyl) | 60-min post-anesthesia-From the start to the end of the constant-workload cycling test (limited by symptoms of the patients) - Every 2-min during exercise | 
| Effort perception | Leg fatigue and dyspnea perception (Borg scale scores) will be monitored periodically every 2-min during the cycling test and will be compared between the two conditions (placebo vs. fentanyl) | 60-min post-anesthesia-From the start to the end of the constant-workload cycling test (limited by symptoms of the patients) - Every 2-min during exercise | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic pulmonary obstructive disease, Muscle dysfunction, Exercise intolerance, Muscle afferents, Ventilation