Clinical trial NCT04854863: Respiratory Muscles After Hospitalisation for COVID-19
Official title: Respiratory Muscle Function After Hospitalisation for COVID-19 -Pathophysiological Model on Severity, Determinants and Clinical Consequences of Respiratory Muscle Strength Impairment in Patients Who Had Been Hospitalised for COVID-19-
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Covid19
Diaphragm Injury
Lead sponsor: RWTH Aachen University
Sponsor class: OTHER
First posted: 2021-04-22
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The aim of the present project is to comprehensively measure respiratory muscle function and strength in patients who survived a hospitalisation for a severe COVID-19-infection (25 with a severe course requiring mechanical ventilation in the intensive care unit, 25 with a moderate-severe course requiring administration of supplemental oxygen only, respectively)

Brief summary: Fatigue and exercise intolerance after survived COVID-19-infection might be related to weakness of the respiratory muscles especially following invasive mechanical ventilation in the Intensive Care Unit.

The aim of the project is to measure respiratory muscle function and strength in our respiratory physiology laboratory (Respiratory Physiology Laboratory, Department of Pneumology and Intensive Care Medicine, Head: Professor Michael Dreher) in patients who survived a severe COVID-19-infection (25 with a severe course requiring mechanical ventilation in the intensive care unit, 25 with a moderate-severe course requiring administration of supplemental oxygen only, respectively).

Based on this data the aim is to develop a model which determines the severity, pathophysiology and clinical consequences of respiratory muscle dysfunction in patients who had been hospitalised for COVID-19.

This will potentially prove the importance of a dedicated pulmonologic rehabilitation with respiratory muscle strength training in patients who had been hospitalised for COVID-19.

Detailed description: The aim of the present project is to comprehensively measure respiratory muscle function and strength in patients who survived a hospitalisation for a severe COVID-19-infection (25 with a severe course requiring mechanical ventilation in the intensive care unit, 25 with a moderate-severe course requiring administration of supplemental oxygen only, respectively).

We intend to recruit 50 patients during their regular follow up appointments (12 months and 24 months after their discharge from the hospital) in our pulmonology outpatient-clinic. Patients fulfilling the criterions of inclusion and exclusion will be included.

Patients will undergo a series of measurements on one day in our respiratory physiology laboratory (Respiratory Physiology Laboratory, Department of Pneumology and Intensive Care Medicine, Head: Professor Michael Dreher). Patients will be asked to complete a questionnaire, followed by some examinations comprising spirometry by bodyplethysmography, exercise endurance, capillary blood gas analyses, measurement of maximum inspiratory and expiratory mouth pressures, dynamometric measurement of arm and leg strength, diaphragm ultrasound, magnetic stimulation of the phrenic and lower thoracic nerves with invasive recording of twitch transdiaphragmatic pressure and markers of systemic inflammation based on in depth analyses of blood samples that will be obtained.

Based on this data the aim is to develop a model which determines the severity, pathophysiology and clinical consequences of respiratory muscle dysfunction in patients who had been hospitalised for COVID-19.

This will potentially prove the importance of a dedicated pulmonologic rehabilitation with respiratory muscle strength training in patients who had been hospitalised for COVID-19.

Eligibility criteria: Inclusion Criteria:

* 50 patients with survived COVID-19-infection (25 with a severe course requiring mechanical ventilation in the intensive care unit, 25 with a moderate-severe course requiring administration of supplemental oxygen only, respectively)
* 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
* Bound to a wheel chair
* Patients who are mentally and physically unable to consent and participate into the study
* Patients in an interdependence or with an employment contract with the principal investigator, Co-PI or his deputy.
* Emergency hospital stay in the last 4 weeks preceding the day of the measurements

Primary outcomes:
measure: Twitch transdiaphragmatic pressure in response to supramaximal magnetic stimulation of the phrenic nerve roots
timeFrame: 2 years
measure: Respiratory mouth pressures
timeFrame: 2 years
Secondary outcomes:
measure: Diaphragm ultrasound
timeFrame: 2 years
measure: Exercise intolerance
timeFrame: 2 years
measure: Analyses of markers of systemic inflammation (interleukin levels in ng/ml, TNF alpha in ng/ml, CRP in mg/L; immune phenotyping of inflammatory cells, most importantly whilte blood cell subtypes in %)
timeFrame: 2 years
measure: Lung function
timeFrame: 2 years
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Jens Spiesshoefer
state: NRW
Study officials:
affiliation: RWTH Aachen University
name: Michael Dreher, Professor
role: STUDY_DIRECTOR
affiliation: RWTH Aachen University
name: Jens Spiesshoefer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: RWTH Aachen University
name: Janina Friedrich, MD
role: STUDY_CHAIR
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, 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.
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.