Respiratory Muscles After Inspiratory Muscle Training After COVID-19

Study Overview
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Brief Summary
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It is the aim of the current (follow-up) project for the first time in post-COVID-19 patients who continue to complain of shortness of breath and for whom there is no other explanation than possibly proven diaphragmatic weakness, to determine the effects of 6 weeks of IMT/diaphragm training on diaphragm strength and shortness of breath.

Detailed Description
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Breathing is a complex process involving muscular, neurological and chemical processes in the body. Herein, the respiratory muscles play a very important role. The respiratory muscles are the muscle groups that cause the expansion and contraction of the chest during inhalation and exhalation. The most important respiratory muscle is the diaphragm. It is known that long-term ventilation in the intensive care unit weakens the respiratory muscles, since the work of the muscles is taken over by the ventilation devices and the muscles are not trained over a long period of time. As recently shown, COVID-19 disease can lead to diaphragmatic weakness even in the absence of ventilation. In this project (CTCA 20-515) the present investigators demonstrated that several patients after COVID-19 suffer from diaphragmatic weakness. Specifically, diaphragmatic weakness also related to shortness of breath complained about by patients and currently not otherwise explainable. The so-called inspiratory muscle training (IMT or diaphragm training) is known in pneumological rehabilitation for years. In the current project, after the training has been explained, the patient is asked to breathe against resistance at home using a small mouthpiece and a small device several times (twice) a day and several times a week (each day). This procedure is considered safe and very effective in training the diaphragm. Accordingly, it is the aim of the current (follow-up) project for the first time in post-COVID patients who continue to complain of shortness of breath and for whom there is no other explanation than possibly the proven diaphragmatic weakness, to determine the effects of 6 weeks of IMT/diaphragm training on diaphragm strength and on shortness of breath. At the beginning and at the end of the 6 weeks of training, the present investigators would carry out the all-encompassing measurement of diaphragm force, which is known to patients and explained again below. Furthermore, the present investigators would invite patients twice a week to optimize the training together (for a maximum of 1 hour per appointment). This would take place once a week in the present investigators laboratory for respiratory physiology and the training would be improved it if necessary, once a week. The training would end after 6 weeks and the present investigators would measure diaphragm function again 6 weeks after the training, i.e. a third time in total, to determine whether the effects seen continue to be present after the training. After that, the study ends. The present investigators would offer the treatment arm (the 9/18 patients) in whom diaphragm endurance training was carried out as a control of the diaphragmatic strength training to carry out strength training after the measurement 6 weeks after the end of the therapy (outside of this study here as a purely clinical therapy). The training itself includes 2 x 30 breathing cycles per day. Patients can divide these 2 x 30 breathing cycles freely, i.e. specifically train 1 x 30 breathing cycles in the morning and 1 x 30 breathing cycles in the afternoon. The whole training should take place daily, 7 days a week. Once a week the present investigators get a picture of the patient's training, pay attention to shortness of breath, potential for adaptation (also specifically for even stronger training, if tolerated by the patients, increase in training, i.e. the breathing resistance that patients would have to overcome when inhaling ). In the control arm of the study, this force adjustment would not take place, i.e. it is an endurance training of the diaphragm with, however, also the control dates of the training twice a week. At least in the 6 weeks of the study (see above).

Official Title
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Respiratory Muscles After Inspiratory Muscle Training in Patients After COVID-19 With Persistent Dyspnea and Respiratory Muscle Dysfunction

Conditions
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COVID-19, Diaphragm Injury

Intervention / Treatment
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* Device: Inspiratory Muscle Training (IMT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 patients with survived COVID-19, persistent otherwise unexplainable dyspnoea and proven diaphragm dysfunction Patients aged at least 18 years, who are mentally and physically able to consent and participate into the study Exclusion Criteria: Diagnosis of another disease, which causes a permanent increase in carbon dioxide level in the blood (chronic hypercapnia) or a permanent combined lung weakness (particularly a neuromuscular disease) Body-mass-index (BMI) >40 Expected absence of active participation of the patient in study-related measurements Alcohol or drug abuse Metal implant in the body that is not MRI compatible (NON MRI compatible pacemaker, implantable defibrillator, cervical implants, e.g. brain pacemakers etc.) Slipped disc Epilepsy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Diaphragm Strength Training<br> | Device: Inspiratory Muscle Training (IMT)<br>* The training itself includes 2 x 30 breathing cycles per day. The whole training should take place daily, 7 days a week. The initial training intensity in the treatment arm (resistance of the respiratory muscle training) is set to 50% of the maximum respiratory muscle strength (measured using PImax). Once a week the present investigators get a picture of patient's training, pay attention to shortness of breath, potential for adaptation. In the control arm of the study, this force adjustment would not take place, i.e. it is an endurance training of the diaphragm (10% of PI Max over the whole 6 weeks) with, however, also the control dates of the training twice a week. At least in the 6 weeks of the study (see above).<br>|
| Sham Comparator: Diaphragm Endurance Training<br> | Device: Inspiratory Muscle Training (IMT)<br>* The training itself includes 2 x 30 breathing cycles per day. The whole training should take place daily, 7 days a week. The initial training intensity in the treatment arm (resistance of the respiratory muscle training) is set to 50% of the maximum respiratory muscle strength (measured using PImax). Once a week the present investigators get a picture of patient's training, pay attention to shortness of breath, potential for adaptation. In the control arm of the study, this force adjustment would not take place, i.e. it is an endurance training of the diaphragm (10% of PI Max over the whole 6 weeks) with, however, also the control dates of the training twice a week. At least in the 6 weeks of the study (see above).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Twitch transdiaphragmatic pressure in response to supramaximal magnetic stimulation of the phrenic nerve roots (Unit: Pressure in cmH2O) |  | Assessed at baseline | 
| Twitch transdiaphragmatic pressure in response to supramaximal magnetic stimulation of the phrenic nerve roots (Unit: Pressure in cmH2O) |  | Assessed after 6 weeks of IMT | 
| Twitch transdiaphragmatic pressure in response to supramaximal magnetic stimulation of the phrenic nerve roots (Unit: Pressure in cmH2O) |  | Assessed 6 weeks after IMT | 
| Respiratory mouth pressures | Measurement of respiratory (inspiratory and expiratory) mouth pressures (Unit: Pressure in cmH2O) | Assessed at baseline | 
| Respiratory mouth pressures | Measurement of respiratory (inspiratory and expiratory) mouth pressures (Unit: Pressure in cmH2O) | Assessed after 6 weeks of IMT | 
| Respiratory mouth pressures | Measurement of respiratory (inspiratory and expiratory) mouth pressures (Unit: Pressure in cmH2O) | Assessed 6 weeks after IMT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diaphragm and Intercostal ultrasound | Thickening fraction (Unit: %) | Assessed at baseline | 
| Diaphragm and Intercostal ultrasound | Thickening fraction (Unit: %) | Assessed after 6 weeks of IMT | 
| Diaphragm and Intercostal ultrasound | Thickening fraction (Unit: %) | Assessed 6 weeks after IMT | 
| Exercise intolerance | Dyspnea (Borg dyspnea scale; Unit 1-10 with higher values indicating more severe dyspnea) | Assessed at baseline | 
| Exercise intolerance | Dyspnea (Borg dyspnea scale; Unit 1-10 with higher values indicating more severe dyspnea) | Assessed after 6 weeks of IMT | 
| Exercise intolerance | Dyspnea (Borg dyspnea scale; Unit 1-10 with higher values indicating more severe dyspnea) | Assessed 6 weeks after IMT | 
| Lung function | Comprehensive assessment of lung function (most importantly forced vital capacity; Unit Liters) | Assessed at baseline | 
| Lung function | Comprehensive assessment of lung function (most importantly forced vital capacity; Unit Liters) | Assessed after 6 weeks of IMT | 
| Lung function | Comprehensive assessment of lung function (most importantly forced vital capacity; Unit Liters) | Assessed 6 weeks after IMT | 
| Electromyography of diaphragm and accessory respiratory muscle activity | Activity of the respiratory muscles (Unit: % with higher values indicating higher activity of the respiratory muscles) | Assessed at baseline | 
| Electromyography of diaphragm and accessory respiratory muscle activity | Activity of the respiratory muscles (Unit: % with higher values indicating higher activity of the respiratory muscles) | Assessed after 6 weeks of IMT | 
| Electromyography of diaphragm and accessory respiratory muscle activity | Activity of the respiratory muscles (Unit: % with higher values indicating higher activity of the respiratory muscles) | Assessed 6 weeks after IMT |