Diaphragmatic Function as a Biomarker (DFUNBIO)

Diaphragmatic Function as a Biomarker in Patients With Respiratory Diseases

Dyspnea is among the most common symptoms in patients with respiratory diseases such as Asthma, chronic obstructive pulmonary disease (COPD), Fibrosis, and Pulmonary Hypertension. However, the pathophysiology and underlying mechanisms of dyspnea in patients with respiratory diseases are still poorly understood. Diaphragm dysfunction might be highly prevalent in patients with dyspnea and respiratory diseases. The association of diaphragm function and potential prognostic significance in patients with respiratory diseases has not yet been investigated.

Study Overview

• Status: Recruiting
• Conditions: Fibrosis; Asthma; Pulmonary Hypertension; COPD; Dyspnea; Dyspnea; Asthmatic
• Intervention / Treatment: Diagnostic test: Diaphragm Ultrasound; Diagnostic test: Intercostal Muscle Ultrasound; Diagnostic test: Borg scale; Diagnostic test: MRC Breathlessness Scale; Diagnostic test: Respiratory Questionaire; Diagnostic test: GINA classification of Asthma; Diagnostic test: Measurement of respiratory mouth pressure; Diagnostic test: SNIP; Diagnostic test: 6-minute walking distance; Diagnostic test: 60 seconds sit-to-stand test; Diagnostic test: Electromyography; Diagnostic test: Lung Function; Diagnostic test: CAT-Questionnaire; Diagnostic test: European Society of Cardiology (ESC)/ European Respiratory Society (ERS) risk group

Detailed Description

The aim of the present project is to comprehensively measure respiratory muscle function and strength in patients with respiratory diseases. The investigators attempt to recruit 800 patients across four disease groups (Asthma, COPD, Fibrosis, and Pulmonary Hypertension) and the investigators intend to measure diaphragm and accessory respiratory muscle function and strength, lung function, and exercise tolerance, as well as the participants' symptom burden during one day at baseline in the investigators' lab. Thereafter, the investigators will follow up on patients by phone 3 months, 6 months, 12 months and 18 months after the investigators have seen them in the investigators' lab. Based on these results, not only the association between dyspnea exercise tolerance and diaphragm function in patients with respiratory diseases can be assessed, but also the prognostic significance of diaphragm dysfunction in these patients can be determined. As such, hospitalization and exacerbation requiring the intake of steroids will be assessed and followed up on by phone, and therefore the prognostic significance of diaphragm dysfunction in predicting hospitalization and the intake of steroids can be determined.

• Study Type: Observational
• Enrollment (Estimated): 800

Contacts and Locations

• Study Contact: Name: Jens Spiesshoefer, MD; Phone Number: 0049 2418037036; Email: jspiesshoefer@ukaachen.de

Study Locations

• Germany
  • North Rhine-westphalia
    • Aachen, North Rhine-westphalia, Germany, 52074
      • Recruiting
      • RWTH Aachen University Hospital
      • Contact: Jens Spiesshoefer, PhD; Phone Number: +492418037036; Email: jspiesshoefer@ukaachen.de
      • Contact: Binaya Regmi, MD; Phone Number: +492418037065; Email: bregmi@ukaachen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

800 patients, 4 groups

Description

Inclusion Criteria:

• patient has one of the following lung diseases: COPD, bronchial asthma, pulmonary fibrosis, pulmonary hypertension
• is 18 years or older
• is mentally and physically able to understand the study and to follow instructions
• are legally competent
• signed declaration of consent

Exclusion Criteria:

• BMI > 35
• current or treatments or diseases in the past which could influence the evaluation of the study
• Expected lack of willingness to actively participate in study-related measures
• alcohol or drug abuse
• disc herniation/prolapse
• epilepsy
• wheelchair bound
• in custody due to an official or court order
• in a dependent relationship or employment relationship with investigating physician or one of their deputy
• emergency inpatient hospital stay within 4 weeks before study-specific examinations

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with Asthma	Diagnostic test: Diaphragm Ultrasound; Ultrasound of the Diaphragm at the end of inspiration and expiration; Diagnostic test: Intercostal Muscle Ultrasound; Ultrasound of the Intercostal Muscles at the end of inspiration and expiration; Diagnostic test: Borg scale; Questionnaire for Perceived Exertion (Borg Rating of Perceived Exertion Scale); Diagnostic test: MRC Breathlessness Scale; The MRC Dyspnoea Scale allows the patients to indicate the extent to which their breathlessness affects their mobility.; Diagnostic test: Respiratory Questionaire; Specialized respiratory questionnaire with different domains (Emotional Domain, Dyspnea Domain, Mastery Domain, Fatigue Domain); Diagnostic test: GINA classification of Asthma; Patients are classified according to the GINA classification of Asthma.; Diagnostic test: Measurement of respiratory mouth pressure; Inspiratory and expiratory Measurement of respiratory mouth pressure; Diagnostic test: SNIP; Measurement of Sniff Nasal Inspiratory Pressure; Diagnostic test: 6-minute walking distance; The maximum walking distance achieved in 6 minutes; Diagnostic test: 60 seconds sit-to-stand test; number of repetitions achieved in sitting down and standing up in 60 seconds; Diagnostic test: Electromyography; electromyography of the muscles of respiration via superficial electrodes; Diagnostic test: Lung Function; Measurement of lung function via body plethysmography
Patients with COPD	Diagnostic test: Diaphragm Ultrasound; Ultrasound of the Diaphragm at the end of inspiration and expiration; Diagnostic test: Intercostal Muscle Ultrasound; Ultrasound of the Intercostal Muscles at the end of inspiration and expiration; Diagnostic test: Borg scale; Questionnaire for Perceived Exertion (Borg Rating of Perceived Exertion Scale); Diagnostic test: MRC Breathlessness Scale; The MRC Dyspnoea Scale allows the patients to indicate the extent to which their breathlessness affects their mobility.; Diagnostic test: Respiratory Questionaire; Specialized respiratory questionnaire with different domains (Emotional Domain, Dyspnea Domain, Mastery Domain, Fatigue Domain); Diagnostic test: Measurement of respiratory mouth pressure; Inspiratory and expiratory Measurement of respiratory mouth pressure; Diagnostic test: SNIP; Measurement of Sniff Nasal Inspiratory Pressure; Diagnostic test: 6-minute walking distance; The maximum walking distance achieved in 6 minutes; Diagnostic test: 60 seconds sit-to-stand test; number of repetitions achieved in sitting down and standing up in 60 seconds; Diagnostic test: Electromyography; electromyography of the muscles of respiration via superficial electrodes; Diagnostic test: Lung Function; Measurement of lung function via body plethysmography; Diagnostic test: CAT-Questionnaire; COPD Assessment Test (CAT)
Patients with Fibrosis	Diagnostic test: Diaphragm Ultrasound; Ultrasound of the Diaphragm at the end of inspiration and expiration; Diagnostic test: Intercostal Muscle Ultrasound; Ultrasound of the Intercostal Muscles at the end of inspiration and expiration; Diagnostic test: Borg scale; Questionnaire for Perceived Exertion (Borg Rating of Perceived Exertion Scale); Diagnostic test: MRC Breathlessness Scale; The MRC Dyspnoea Scale allows the patients to indicate the extent to which their breathlessness affects their mobility.; Diagnostic test: Respiratory Questionaire; Specialized respiratory questionnaire with different domains (Emotional Domain, Dyspnea Domain, Mastery Domain, Fatigue Domain); Diagnostic test: Measurement of respiratory mouth pressure; Inspiratory and expiratory Measurement of respiratory mouth pressure; Diagnostic test: SNIP; Measurement of Sniff Nasal Inspiratory Pressure; Diagnostic test: 6-minute walking distance; The maximum walking distance achieved in 6 minutes; Diagnostic test: 60 seconds sit-to-stand test; number of repetitions achieved in sitting down and standing up in 60 seconds; Diagnostic test: Electromyography; electromyography of the muscles of respiration via superficial electrodes; Diagnostic test: Lung Function; Measurement of lung function via body plethysmography
Patients with Pulmonary Hypertension	Diagnostic test: Diaphragm Ultrasound; Ultrasound of the Diaphragm at the end of inspiration and expiration; Diagnostic test: Intercostal Muscle Ultrasound; Ultrasound of the Intercostal Muscles at the end of inspiration and expiration; Diagnostic test: Borg scale; Questionnaire for Perceived Exertion (Borg Rating of Perceived Exertion Scale); Diagnostic test: MRC Breathlessness Scale; The MRC Dyspnoea Scale allows the patients to indicate the extent to which their breathlessness affects their mobility.; Diagnostic test: Respiratory Questionaire; Specialized respiratory questionnaire with different domains (Emotional Domain, Dyspnea Domain, Mastery Domain, Fatigue Domain); Diagnostic test: Measurement of respiratory mouth pressure; Inspiratory and expiratory Measurement of respiratory mouth pressure; Diagnostic test: SNIP; Measurement of Sniff Nasal Inspiratory Pressure; Diagnostic test: 6-minute walking distance; The maximum walking distance achieved in 6 minutes; Diagnostic test: 60 seconds sit-to-stand test; number of repetitions achieved in sitting down and standing up in 60 seconds; Diagnostic test: Electromyography; electromyography of the muscles of respiration via superficial electrodes; Diagnostic test: Lung Function; Measurement of lung function via body plethysmography; Diagnostic test: European Society of Cardiology (ESC)/ European Respiratory Society (ERS) risk group; Patients with pulmonary hypertension are classified according to the ESC/ERS risk group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dyspnea Borg scale 1 to 10	Borg scale before and after "6 minute walking distance" test. Lower scores show fewer dyspnea, higher scores indicate more dyspnea.	6 months recruiting
Dyspnea Borg scale 1 to 10	Borg scale before and after "6 minute walking distance" test. Lower scores show fewer dyspnea, higher scores indicate more dyspnea.	follow up 3 months after recruitment
Dyspnea Borg scale 1 to 10	Borg scale before and after "6 minute walking distance" test. Lower scores show fewer dyspnea, higher scores indicate more dyspnea.	follow up 6 months after recruitment
Dyspnea Borg scale 1 to 10	Borg scale before and after "6 minute walking distance" test. Lower scores show fewer dyspnea, higher scores indicate more dyspnea.	follow up 12 months after recruitment
Dyspnea Borg scale 1 to 10	Borg scale before and after "6 minute walking distance" test. Lower scores show fewer dyspnea, higher scores indicate more dyspnea.	follow up 18 months after recruitment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6 minute walking distance in m	Measurement of achieved walking distance in 6 minutes	6 months recruiting
Sit-to stand-test (60 seconds)	Measurement of achieved repetitions of standing up and sitting down from an initial seated position in 60 seconds.	6 months recruiting
New York Heart Association (NYHA) classification scale 1 to 4	Patients are linked to a NYHA degree. Lower scores show fewer dyspnea, higher scores indicate more dyspnea.	6 months recruiting, follow up up to 18 months after last recruitment
Modified Medical Research Council (MRC) Breathlessness Scale 1 to 5	Patients are assessed and grouped according to their MRC Breathlessness Scale. Lower scores show fewer dyspnea, higher scores indicate more dyspnea.	6 months recruiting, follow up up to 18 months after last recruitment
Chronic Respiratory Questionnaire (CRQ)	Assessments of different domains (Emotional Domain, Dyspnea Domain, Mastery Domain, Fatigue Domain) in a standardized questionnaire on a scale from 1 to 7. The scores for each question of each dimension are added together and divided by the number of completed questions in each domain. In general, higher scores mean a worse outcome and lower scores mean a better outcome. For the dyspnea domain for example, a high score means that patients have less dyspnea, and a low score means that patients have more dyspnea.	6 months recruiting, follow up up to 18 months after last recruitment
COPD Assessment Test (CAT-Questionnaire) from 0 to 40 points.	Patients are evaluated and placed into the corresponding groups. Lower scores show fewer dyspnea, higher scores indicate more dyspnea.	6 months recruiting, follow up up to 18 months after last recruitment
Global Initiative for Asthma (GINA) classification	Patients are assessed and grouped as mild, moderate, or severe according to the GINA classification.	6 months recruiting, follow up up to 18 months after last recruitment
Body Plethysmography	TLC (Total lung capacity) in percent predicted.	6 months recruiting
Diaphragm Thickening Ratio (DTR) in percent	Via ultrasound, the diaphragm thickening ratio (DTR) was calculated as thickness at total lung capacity (TLC) divided by thickness at functional residual capacity (FRC).	6 months recruiting
Diaphragm thickness at Total lung capacity (TLC)	Via ultrasound, the diaphragm thickness at TLC is measured at the maximum point of inspiration.	6 months recruiting
Diaphragm thickness at functional capacity (FRC)	Via ultrasound, the diaphragm thickness at FRC is measured after a normal expiration.	6 months recruiting
Diaphragm ultrasound sniff velocity in cm/s	Via ultrasound, the diaphragm sniff velocity was assessed during tidal breathing and following a maximum sniff.	6 months recruiting
Intercostal Muscle ultrasound thickness at Total lung capacity (TLC) in cm	Via ultrasound, the intercostal thickness at TLC is measured at the maximum point of inspiration.	6 months recruiting
Intercostal Muscle ultrasound thickness at functional capacity (FRC) in cm	Via ultrasound, the intercostal thickness at FRC is measured after a normal expiration.	6 months recruiting
Intercostal Muscle Thickening Ratio in percent	Via ultrasound, the intercostal muscle thickening ratio was calculated as thickness at total lung capacity (TLC) divided by thickness at functional residual capacity (FRC).	6 months recruiting
Maximum Inspiratory Pressure (MIP) in percent predicted	Measurement of Maximum Inspiratory Pressure	6 months recruiting
Maximum Expiratory Pressure (MEP) in percent predicted	Measurement of Maximum Expiratory Pressure	6 months recruiting
Sniff Nasal Inspiratory Pressure (SNIP) in percent predicted	Measurement of Sniff Nasal Inspiratory Pressure	6 months recruiting
Blood Gas Analysis in cmH2O	oxygen partial pressure (pO2)	6 months recruiting
Blood Gas Analysis in cmH2O	carbon dioxide partial pressure (pCO2)	6 months recruiting
Blood Gas Analysis	pH scale	6 months recruiting
Blood Gas Analysis in mmol/l	Base Excess	6 months recruiting
Blood Gas Analysis in (I1/s) percent	Base Excess	6 months recruiting
Electromyography (EMG)	Measurement of electrical activity during different breathing maneuvers (Sniff, Cough, Valsalva, Mueller) via superficial electrodes placed on the diaphragm and accessory respiratory muscles (Sternocleidomastoideus muscle, intercostal muscles).	6 months recruiting

Collaborators and Investigators

• Sponsor: RWTH Aachen University
• Investigators: Study Director: Michael Dreher, MD, Uniklinik RWTH Aachen; Study Chair: Binaya Regmi, MD, Uniklinik RWTH Aachen; Principal Investigator: Jens Spiesshoefer, MD, Uniklinik RWTH Aachen; Study Chair: Mustafa Elfeturi, Uniklinik RWTH Aachen; Study Chair: Benedikt Jörn, Uniklinik RWTH Aachen; Study Chair: Faniry Ratsimba, Uniklinik RWTH Aachen; Study Chair: Felix Wagner, Uniklinik RWTH Aachen

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2023
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: May 18, 2023
• First Submitted That Met QC Criteria: June 5, 2023
• First Posted (Actual): June 15, 2023

Study Record Updates

• Last Update Posted (Actual): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 21, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: COPD; asthma; pulmonary hypertension; fibrosis; dyspnea; pneumology
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Signs and Symptoms, Respiratory; Fibrosis; Hypertension; Hypertension, Pulmonary; Dyspnea
• Other Study ID Numbers: RWTHAachenU

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No