Different Modalities of Exercise Training in COPD With Chronic Respiratory Failure (CRF)

Study Overview
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Brief Summary
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Advanced Chronic Obstructive Pulmonary Disease (COPD) is a condition with a negative prognosis that causes symptoms such as wheezing and fatigue that dramatically reduce the quality of life of the person with the disease. Typically, the advanced stage of COPD is characterized by a fluctuating pattern and recurrent hospitalizations, and by a vicious circle in which dyspnoea increases and exercise tolerance reduces, causing depression with social isolation, low quality of life and increased risk of death. Muscle dysfunction in these patients contributes together with dynamic hyperinflation to increased fatigue and dyspnoea during exercise, leading to early interruption of exertion, before reaching the maximal aerobic capacity. The European and American guidelines of the American Thoracic Society / European Respiratory Society relating to the patient with COPD emphasize the need for the patient to undergo Respiratory Rehabilitation (RR) programs. The RR should include training programs as they improve exercise capacity, dyspnoea and quality of life more than programs that do not include training. To our knowledge, no study has been performed in COPD with chronic respiratory failure (CRF) patients to evaluate the effects of High Interval Training compared to continuous submaximal training. Moreover, no different interval training protocols have been compared. However, studies conducted on healthy subjects or on other pathologies, show how the interval training protocol induces, in a specific and diversified way, physiological modifications to the cardio-respiratory and muscular systems. In COPD patients with respiratory failure with marked muscular dysfunction and associated systemic changes (systemic inflammation, vascular changes, pulmonary hypertension, right heart failure, etc.), the evaluation of the best training program would reinforce the rehabilitative indications not yet fully proposed in the Guidelines. Moreover, the evaluation of the response to different training stimuli could provide important information on the reversibility of the intolerance to the effort in this patient population. Primary aim of this study will be to evaluate the physiological effects on exercise tolerance of three training modalities performed in an intra-hospital setting (classic endurance training compared to two high-intensity interval programs - Long Interval Training and Short Interval training) in a population of COPD patients with chronic hypoxemic respiratory failure.

Detailed Description
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Advanced (Chronic Obstructive Pulmonary Disease) COPD is a condition with a negative prognosis that causes symptoms such as wheezing and fatigue that dramatically reduce the quality of life of the person with the disease. Typically, the advanced stage of COPD is characterized by a fluctuating pattern and recurrent hospitalizations, and by a vicious circle in which dyspnoea increases and exercise tolerance reduces, which in turn causes depression and associated social isolation, low quality of life and increased risk of death. Muscle dysfunction in these patients contributes together with dynamic hyperinflation to increased fatigue and dyspnoea during exercise, leading to early interruption of exertion, before reaching maximum aerobic capacity. The European and American guidelines of the American Thoracic Society / European Respiratory Society relating to the patient with Chronic Obstructive Pulmonary Disease (COPD) emphasize the need for the patient to undergo Respiratory Rehabilitation (RR) programs. The RR should include training programs as they improve exercise capacity, dyspnoea and quality of life more than programs that do not include training. However, although there are many studies referring to the benefits of physical exercise in patients with COPD with mild-to-moderate severity, the recent guidelines provide few recommendations for types of training and its efficacy for patients with advanced disease that have already developed Chronic Respiratory Failure (CRF) and use of Long Term Oxygen Therapy (LTOT). Thanks to a retrospective study on 1047 patients, the Authors have previously shown that patients with COPD with CRF respond to a rehabilitation program (in terms of exercise tolerance, blood gases, dyspnoea and quality of life) as well as COPD patients without CRF. A recent meta-analysis conducted by Paneroni et al. supports the effectiveness of exercise in improving quality of life and functional capacity in patients with severe COPD (FEV1 <35%), with or without CRF. The study showed that so far the training proposed to these patients is mainly of moderate-intensity endurance and performed primarily through the continuous use of exercise bikes or free walking. In a similar way to patients with moderate or mild severity, the setting of the exercise was mainly proposed using a speed or a load that approximates around 70% of the maximum value reached in an incremental test. Regarding the type of exercise to be used in patients with COPD, several recent papers suggest the opportunity to use interval training even in high intensity. The purpose of the High Interval Training is to repeatedly stress the cardio-respiratory and muscular system, above what is normally required for normal activities, through bouts of high intensity and short duration exercise. In subjects with COPD, this type of training could guarantee a delay in the development of the dynamic hyperinflation mechanism typical of the pathology and could guarantee greater physiological modifications regarding the classical submaximal continuous training. Despite some physiological studies that have tested this effect, the results of the clinical application of these interventions appear - in subjects with moderate COPD - similar to that got with continuing training. However, the protocols proposed to date appear to be diversified in terms of approach, especially concerning the intensity and duration of the active and passive phases. To our knowledge, no study has been performed in COPD with CRF patients to evaluate the effects of High Interval Training compared to continuous submaximal training and no protocols on different interval training have been compared. Indeed, studies conducted on healthy subjects or on other pathologies, show how the interval training protocol induces, in a specific and diversified way, physiological modifications to the cardiorespiratory and muscular systems. In patients with respiratory failure with marked muscular dysfunction and associated systemic changes (systemic inflammation, vascular changes, pulmonary hypertension, right heart failure, etc.), the evaluation of the best training program would reinforce the rehabilitative indications not yet fully proposed in the Guidelines. Moreover, the evaluation of the response to different training stimuli could provide important information on the reversibility of the intolerance to the effort in this patient population.

Official Title
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Comparison of Clinical and Physiological Response Among Three Modalities of Exercise Training in COPD With Chronic Respiratory Failure (CRF)

Conditions
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Copd, Chronic Hypoxemic Respiratory Failure

Intervention / Treatment
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* Other: Endurance Training
* Other: Long High Intensity Interval Training
* Other: Short High Intensity Interval Training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age> 50 years clinical definition of COPD according to GOLD guidelines (10) with FEV1 / FVC G 70% and FEV1 <50% of the above PaO2 in air-ambient lower than 60 mmHg evaluated through arterial blood gas analysis oxygen therapy prescription for more than 18 hours/ day for at least one month clinical stable condition Exclusion Criteria: presence of pulmonary diseases other than COPD respiratory tract infections in the last 4 weeks termination

Ages Eligible for Study
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Minimum Age: 51 Years

Sexes Eligible for Study
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All

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

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Comparator<br>This is the constant-load Endurance Training (ET) group which will constitute the control group. | Other: Endurance Training<br>* These patients will perform an aerobic exercise with a moderate intensity cycle ergometer. The exercise session on an exercise bike will last 33 minutes at a constant load, starting from an intensity equal to the load of 60% of the maximum load (max watt) achieved at the incremental test. Working volume = 60 X 33 = 1980<br>* Other names: Active Comparator;|
| Experimental: Long High Intensity Interval Training<br>This is the Long High Intensity Interval Training (Long-HIIT) group. | Other: Long High Intensity Interval Training<br>* The patients assigned to the Long-HIIT group will perform a 32-minute interval work with 4x4 protocol (active phase x passive phase) performing 4 minutes at an intensity of 80-85% of the Max Watt (active phase) spaced from 4 minutes to 40% of the Max Watt (passive phase). The goal of high intensity work will be to bring the heart rate to a level close to 85-90% of the maximum cardiac frequency achieved in the incremental exercise test. If this target is not reached within the session, the load of the next one will be increased in the following session with 10 watt steps. Working volume = 16 X 85 + 16 x 40 = 2000<br>* Other names: Experimental 1;|
| Experimental: Short High Intensity Interval Training<br>This is the Short High Intensity Interval Training (Short-HIIT) group. | Other: Short High Intensity Interval Training<br>* The patients assigned to the Short-HIIT group will perform an interval work with initial intensity equal to 100% of the Max Watt highlighted in the incremental exercise stress test in the phase (30 seconds) followed by a passive phase of 30 seconds at 50% of the Max Watt for a period of 26 minutes a day. The intensity will be gradually increased during the sessions with symptom-based progression, according to the protocol of Maltais et al. with steps of 10 watts each increment. Working volume = 13 X 100 + 13 x 50 = 2050<br>* Other names: Experimental 2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in effort tolerance | We will evaluate the time to exhaustion (Tlim) of a Constant Load Endurance Test (CLET) taht will be set at load corresponding to 80% of the Watts max achieved at the incremental cicloergometer test. | at baseline, 1 month and 7 months | 
| Changes in the maximal work load | Another way to evaluate changes in effort tolerance will be to evaluate the maximal work load (Watts max) that patients will achive during a cicloergometer incremental test. | at baseline and 1 month | 
| Changes in walking distance | Another way to evaluate changes in effort tolerance will be to evaluate meters walked during a 6 minute walking test (6MWT). | at baseline, 1 month and 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of drop out patients | To evaluate feasibility of the study, we will calculate the percentage of patients dropped out at the end of the rehabilitation period | at 1 month | 
| Patient's satisfaction: Likert scale | To evaluate feasibility of the study, we will administer to patients a questionnaire of satisfaction at the end of the rehabilitation period. Likert scale will be from 0 to 4, where 0= completely unsatisfied and 4= very satisfied) | at 1 month | 
| Change in dyspnoea | We will evaluated dyspnea by Barthel index Dyspnea, a scale measuring dyspnea during basal activities of daily living (ADL). It is a 10-item scale ranging from 0= absence of dyspnea to 100= maximal dyspnea) | at baseline, 1 month and 7 months | 
| Changes in quadriceps volume | We will evaluate changes in muscle volume (quadricips) by ecography | at baseline, 1 month and 7 months | 
| Change in ADL performance | We will evaluate the activities of daily life through the Glittre-ADL test. This consists in a circuit of 5-serie of activities (lifting a chair, walking, lifting 2 steps, moving the weight up and down from a shelf). We will evaluate the total time spent to complete the performance. | at baseline, 1 month and 7 months | 
| Change in fatigue (physiological evaluation) | We will evaluate the change in force generated by a Maximal Volontary Contraction (MVC) and an Electrically stimulated muscular contractions at rest [Resting Twitch (RT)] of the quadriceps muscle (Q) after a fatiguing task ( CLET). Subjects will be seated upright with a back support. The hip and knee will be flexed at 90 ° and the force will be measured by a force transducer. Electromyographic evaluation: the M waves will be recorded by the Q muscle (vastus lateralis). The EMG signals will be amplified with a bandwidth of 10 Hz-1 kHz and digitized online at a sampling frequency of 5 kHz. Voluntary electromyographic activation of the quadriceps muscle during MVC will be evaluated using a superimposed contraction technique. | at baseline, 1 month and 7 months | 
| Change in fatigue (qualitative evaluation) | For the qualitative evaluation, we will use the Fatigue severity scale that is a 9-item scale ranging from 7= absence of fatigue to 63= maximal presence of fatigue). | at baseline, 1 month and 7 months | 
| Change in Endothelial function | The endothelial function will be evaluated by an ultrasound evaluation of the common femoral artery before and after the application of the short Passive Leg Movement (sPLM) technique. | at baseline, 1 month and 7 months | 
| Change in Balance | To evaluate balance and consequent risk of falls, a Berg scale will be used. Berg scale is composed by 14 balance related tasks, ranging from score 0=worse balance to 56= best balance. | at 1 month and 7 months | 
| Change in quality of life | COPD Assessment Test (CAT) scale will be used. CAT is a 8-item scale, ranging from score 0 to 40 (where 0=best and 40=worse) evaluating quality of life and well-being | 1 month and 7 months | 
| Change in quality of life | MRF scale will be used. MRF is a 28-item questionnaire to assess health outcomes in Chronic Respiratory Failure (CRF). MRF ranges from 26=worse to best = 0 ... | at 1 month and 7 months |