Muscular Rehabilitation by Eccentric Exercise After Severe COVID-19 Infection (CovExc)

Muscular Rehabilitation by Eccentric Exercise After Severe COVID-19 Infection: Research Protocol for Randomized Controlled Trial (CovExc)

With the COVID-19 pandemic, the number of patients to be treated in rehabilitation increased . Hospitalization for severe infection can induce muscular atrophy and muscular dysfunction that persists for several months and rehabilitation capacities may be exceeded. Exercises in eccentric mode could be performed, inducing greater muscular hypertrophy, muscle strength, power and speed than concentric exercises. The goal of this study was to compare functional recovery at 2 months after a training program in eccentric and concentric mode after severe COVID-19. An effective rehabilitation could help reduce costs and duration of care.

This is a prospective, open, controlled randomized study (2 x 60 individuals) performed in 5 centers. Participants will perform 24 exercise sessions on cycloergometer (3 sessions/week, 8 weeks). The experimental group (eccentric) will perform 5 habituation sessions: the initial power of the exercise will be set to 10 Watts and then increased by 10% each session, depending on the muscle tolerance. The training power must correspond to 3 times that of the control group to obtain a similar metabolic stimulation. The control group (concentric) will perform exercise training at an intensity of 60% of the reserve heart rate determined during an initial cardiorespiratory test. The primary outcome will be the change in distance covered during the 6-min walk test between the initial assessment and month 2. Secondary outcomes will include study of sarcopenia, muscle strength, general and muscular fatigue, quality of life, blood metabolomic data, ex vitro data for mitochondrial and histo-biochemical functionality from muscle biopsies of the Vastus Lateralis.

All included participants will be randomly assigned (1:1) using the REDCap software, , at the experimental group or the control group. Participants will perform 24 exercise sessions on cycloergometer (3 sessions/week, 8 weeks). The experimental group (eccentric) will perform 5 habituation sessions: the initial power of the exercise will be set to 10 Watts and then increased by 10% each session, depending on the muscle tolerance. The training power must correspond to 3 times that of the control group to obtain a similar metabolic stimulation. The control group (concentric) will perform exercise training at an intensity of 60% of the reserve heart rate determined during an initial cardiorespiratory test.

Evaluations will be carried out with blinding by investigators different from those involved in the exercise training sessions. Patients will be blinded to the training mode hypothesis.

The experimental group (eccentric) will perform 5 habituation sessions: the initial power of the exercise will be set to 10 Watts and then increased by 10% each session, depending on the muscle tolerance. The training power must correspond to 3 times that of the control group to obtain a similar metabolic stimulation and will be adapted according to the pain felt at the end of the session.

The control group (concentric) will perform exercise training at an intensity of 60% of the reserve heart rate determined during an initial cardiorespiratory test. The power will be adjusted weekly to stay within the target heart rate range.

Participants will perform 24 exercises sessions (30 minutes) with cycloergometer in eccentric mode (while resisting against self-paced pedaling), inducing a greater muscular hypertrophy as compared with concentric mode, the mechanical stimulation being 3 to 4 times greater at the same level metabolic stimulation.

The control group (concentric) will perform exercise training at an intensity of 60% of the reserve heart rate determined during an initial cardiorespiratory test. The power will be adjusted weekly to stay within the target heart rate range.

Average change from baseline walking capacity measured by the 6-minutes walk test (6MWT), expressed in meters. All patients will be asked to cover the longest distance over a 30-meters distance in 6 min with or without stopping and with standardized verbal encouragements according to standard recommendations; to take into account a learning effect, the test will be performed twice, with the longer distance retained, expressed in meters. To prevent adverse effect, pulsed oxygen saturation (% of pSO²) and heart rate (heartbeat per minute) will be monitored continuously throughout the test by using a digital oximeter.

this test consists of assessing balance in a standing position, lifting from a chair (5 stand to-sit repetitions) and measuring 4-m walking speed (20). The patient walks 4 m at a normal and comfortable speed. The "test zone" (4 m) is preceded by an "acceleration zone" (1 m) and is followed by a "deceleration zone" (1 m). The assessor starts and stops the timing when the subject's foot meets the ground when entering and leaving the "test area", respectively.

Evaluating the maximum muscle strength of the quadriceps by Quadriceps Isometric Maximum Strength (QIMS) test

maximum muscle strength of the quadriceps, on the dominant limb, will be measured on a bench: - Strength during isometric contraction (at 90° knee flexion) - Standardized position with the arms crossed on the chest, the absence of back support during the measurement and the maintenance of the hips and the contralateral leg to avoid any compensating movement Three reproducible measurements (±10%) will be taken at 1-min intervals, with the highest value retained.

this test consists of performing 10 knee extensions at 10% QIMS, then gradually increasing the load (10% by 10%) until exhaustion (cannot perform the movement 2 consecutive times). The value retained is the last level (% QIMS) performed.

this scale explores cognitive (10 items), physical (9 items) and psychosocial (2 items) fatigue. The MFIS included 21 items with a total score ranging from 0 to 84 with higher scores indicating a greater impact of quality of life.

This questionnaire explores 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ-5D-5L included 5 items independently scored from 1 to 5 (higher scores indicating a greater impact)and a 0-100 visual analogic scale exploring general health (0 means the worst heath patient can imagine, 100 means the best health patient can imagine).

measurement is in 90° elbow flexion, wrist in neutral position. Three reproducible measurements (± 10%) will be taken at 1-min intervals, with the highest value retained.

Plasma metabolome profile assessed by variation of number of blood metabolites. Changes from baseline to post-training intervention in plasma metabolome profile will be compared between excentric and concentric exercise groups.

Biopsy from the Vastus lateralis will be performed and the variation of cross sectional area measurement of muscle fibers (µm2) will be analysed and compared between excentric and concentric exercise groups from baseline to post-training intervention.

Biopsy from the Vastus lateralis will be performed and the capillarization (variation of capillary to fiber ratio) will be analysed. Muscle adapations from baseline to post-training intervention will be compared between excentric and concentric exercise groups.

Biopsy from the Vastus lateralis will be performed and the evolution of number of satellite cell per muscle fiber will be analysed and compared between excentric and concentric exercise groups from baseline to post-training intervention.

Electrophsyiological stimulation of the quadriceps for the measurement of the neuromuscular activation before, during and after the QIF test. During this test, we measure maximal M-wave, contraction time and torque and the percentage of neuromuscular activation. Neuromuscular activation will be analysed and compared between excentric and concentric exercise groups from baseline to post-training intervention.

An infrared spectroscopy device is localized on the anterior part of the quadriceps. The device measures hemoglobin and desoxyhemoglobin concentration under the placement area. This measure is performed, before, during and after the QIF test. During this test, we measure the hemoglobin and desoxyhemoglobin concentration as well as the tissue saturation index.Quadriceps muscular Oxygen Tissue Saturation will be analysed and compared between excentric and concentric exercise groups from baseline to post-training intervention.

A gaz exchange device records the O2 uptake during the 6 minutes walk test. The O2 uptake efficiency was defined as the volume of O2 per meter used by the participant. An infrared spectroscopy device is localized on the anterior part of the quadriceps. O2 uptake Efficiency during walk test will be analysed and compared between excentric and concentric exercise groups from baseline to post-training intervention.

Inclusion Criteria: Male or female, 18 to 80 years old Diagnosed for SARS-CoV-2 infection (COVID-19) requiring a rehabilitation program at least 1 month after the hospitalization Autonomy in daily life activities 1 month after diagnosis Able to walk for 6 min (discontinuous walking possible) Giving informed written consent to participate in the study Health insurance coverage Exclusion Criteria: Cardiovascular or respiratory contraindication to the rehabilitation program Difficulty to perform an eccentric exercise on a seated ergometer Pregnant or breastfeeding Under guardianship, curatorship or deprived of liberty Taking antivitamin K anticoagulation (muscle biopsy) Refusal to participate

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