Clinical trial NCT05582642: Respiratory Muscles After Inspiratory Muscle Training After COVID-19
Official title: Respiratory Muscles After Inspiratory Muscle Training in Patients After COVID-19 With Persistent Dyspnea and Respiratory Muscle Dysfunction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: COVID-19
Diaphragm Injury
Lead sponsor: RWTH Aachen University
Sponsor class: OTHER
Collaborators: name: Philipps University Marburg
First posted: 2022-10-17
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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

Primary outcomes:
measure: Twitch transdiaphragmatic pressure in response to supramaximal magnetic stimulation of the phrenic nerve roots (Unit: Pressure in cmH2O)
timeFrame: Assessed at baseline
measure: Twitch transdiaphragmatic pressure in response to supramaximal magnetic stimulation of the phrenic nerve roots (Unit: Pressure in cmH2O)
timeFrame: Assessed after 6 weeks of IMT
measure: Twitch transdiaphragmatic pressure in response to supramaximal magnetic stimulation of the phrenic nerve roots (Unit: Pressure in cmH2O)
timeFrame: Assessed 6 weeks after IMT
measure: Respiratory mouth pressures
timeFrame: Assessed at baseline
measure: Respiratory mouth pressures
timeFrame: Assessed after 6 weeks of IMT
measure: Respiratory mouth pressures
timeFrame: Assessed 6 weeks after IMT
Secondary outcomes:
measure: Diaphragm and Intercostal ultrasound
timeFrame: Assessed at baseline
measure: Diaphragm and Intercostal ultrasound
timeFrame: Assessed after 6 weeks of IMT
measure: Diaphragm and Intercostal ultrasound
timeFrame: Assessed 6 weeks after IMT
measure: Exercise intolerance
timeFrame: Assessed at baseline
measure: Exercise intolerance
timeFrame: Assessed after 6 weeks of IMT
measure: Exercise intolerance
timeFrame: Assessed 6 weeks after IMT
measure: Lung function
timeFrame: Assessed at baseline
measure: Lung function
timeFrame: Assessed after 6 weeks of IMT
measure: Lung function
timeFrame: Assessed 6 weeks after IMT
measure: Electromyography of diaphragm and accessory respiratory muscle activity
timeFrame: Assessed at baseline
measure: Electromyography of diaphragm and accessory respiratory muscle activity
timeFrame: Assessed after 6 weeks of IMT
measure: Electromyography of diaphragm and accessory respiratory muscle activity
timeFrame: Assessed 6 weeks after IMT
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: RWTH Aachen University
Study officials:
affiliation: RWTH Aachen University
name: Jens Spiesshoefer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: RWTH Aachen University
name: Binaya Regmi, MD
role: STUDY_CHAIR
affiliation: RWTH Aachen University
name: Michael Dreher, Professor
role: STUDY_DIRECTOR
References:
citation: Daher A, Balfanz P, Aetou M, Hartmann B, Muller-Wieland D, Muller T, Marx N, Dreher M, Cornelissen CG. Clinical course of COVID-19 patients needing supplemental oxygen outside the intensive care unit. Sci Rep. 2021 Jan 26;11(1):2256. doi: 10.1038/s41598-021-81444-9.
citation: Daher A, Balfanz P, Cornelissen C, Muller A, Bergs I, Marx N, Muller-Wieland D, Hartmann B, Dreher M, Muller T. Follow up of patients with severe coronavirus disease 2019 (COVID-19): Pulmonary and extrapulmonary disease sequelae. Respir Med. 2020 Nov-Dec;174:106197. doi: 10.1016/j.rmed.2020.106197. Epub 2020 Oct 20.
citation: Balfanz P, Hartmann B, Muller-Wieland D, Kleines M, Hackl D, Kossack N, Kersten A, Cornelissen C, Muller T, Daher A, Stohr R, Bickenbach J, Marx G, Marx N, Dreher M. Early risk markers for severe clinical course and fatal outcome in German patients with COVID-19. PLoS One. 2021 Jan 29;16(1):e0246182. doi: 10.1371/journal.pone.0246182. eCollection 2021.
citation: Spiesshoefer J, Friedrich J, Regmi B, Geppert J, Jorn B, Kersten A, Giannoni A, Boentert M, Marx G, Marx N, Daher A, Dreher M. Diaphragm dysfunction as a potential determinant of dyspnea on exertion in patients 1 year after COVID-19-related ARDS. Respir Res. 2022 Jul 15;23(1):187. doi: 10.1186/s12931-022-02100-y.
citation: Spiesshoefer J, Henke C, Herkenrath S, Brix T, Randerath W, Young P, Boentert M. Transdiapragmatic pressure and contractile properties of the diaphragm following magnetic stimulation. Respir Physiol Neurobiol. 2019 Aug;266:47-53. doi: 10.1016/j.resp.2019.04.011. Epub 2019 Apr 25.
citation: Spiesshoefer J, Henke C, Herkenrath S, Randerath W, Brix T, Young P, Boentert M. Assessment of Central Drive to the Diaphragm by Twitch Interpolation: Normal Values, Theoretical Considerations, and Future Directions. Respiration. 2019;98(4):283-293. doi: 10.1159/000500726. Epub 2019 Jul 26.
citation: Spiesshoefer J, Herkenrath S, Henke C, Langenbruch L, Schneppe M, Randerath W, Young P, Brix T, Boentert M. Evaluation of Respiratory Muscle Strength and Diaphragm Ultrasound: Normative Values, Theoretical Considerations, and Practical Recommendations. Respiration. 2020;99(5):369-381. doi: 10.1159/000506016. Epub 2020 May 12.