Replaceability of Fluoroscopy and Ultrasound in the Evaluation of Hemidiaphragm Excursion"
Conditions: Diaphragm Disease
Sponsor: University of Aarhus

 
 
 
ASSESSMENT OF DIAPHRAGM'S FUNC-
TION. 
A METHODOLOGICAL STUDY AND A CLINI-
CAL STUDY 
 
 
PROTOCOL VERSION 3 
 
 
 
 
 
 
COLLABORATION BETWEEN CARDIAC DISEASES, INTENSIVE 
CARE, ANESTHESIA AND SURGERY, CARDIOPULMONARY AND 
VASCULAR SURGERY AND PULMONARY DISEASES. 
AARHUS UNIVERSITY HOSPITAL. 
 

 
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CONTENTS 
 
Background  ............................................................................................................................................................................................. 4 
Study 1:  .......................................................................................................................................................................................... 4 
Study 2:  .......................................................................................................................................................................................... 4 
Hypothesis/aim  ........................................................................................................................................................................................ 5 
Titles  ....................................................................................................................................................................................................... 5 
Method  .................................................................................................................................................................................................... 5 
Design  ................................................................................................................................................................................................ 5 
Study 1:  .......................................................................................................................................................................................... 5 
Study 2:  .......................................................................................................................................................................................... 5 
Settings  .............................................................................................................................................................................................. 5 
Participants  ......................................................................................................................................................................................... 5 
Study 1:  .......................................................................................................................................................................................... 5 
Study 2:  .......................................................................................................................................................................................... 5 
Inclusion and exclusion criteria  ........................................................................................................................................................... 6 
Study 1:  .......................................................................................................................................................................................... 6 
Study 2:  .......................................................................................................................................................................................... 6 
Recruitment  ........................................................................................................................................................................................ 6 
Study 1:  .......................................................................................................................................................................................... 6 
Study 2:  .......................................................................................................................................................................................... 7 
Investigations  ...................................................................................................................................................................................... 8 
Study 1:  .......................................................................................................................................................................................... 8 
Study 2:  .......................................................................................................................................................................................... 9 
Endpoints  ........................................................................................................................................................................................... 9 
Study 1:  .......................................................................................................................................................................................... 9 
Study 2:  ........................................................................................................................................................................................ 10 
Strength calculation  .......................................................................................................................................................................... 10 
Study 1:  ........................................................................................................................................................................................ 10 
Study 2:  ........................................................................................................................................................................................ 10 
Summary of desired number of included patients  ......................................................................................................................... 11 
Data registration  ............................................................................................................................................................................... 11 
Data analysis  .................................................................................................................................................................................... 11 
Study 1:  ........................................................................................................................................................................................ 11 
Study 2:  ........................................................................................................................................................................................ 11 
Blinding  ............................................................................................................................................................................................. 11 
Risks and disadvantages  ....................................................................................................................................................................... 11 
Study 1 & 2:  ................................................................................................................................................................................. 12 
Study 1 only:  ................................................................................................................................................................................ 12 
Ethical considerations  ............................................................................................................................................................................ 12 
Study 1:  ........................................................................................................................................................................................ 12 
Study 2:  ........................................................................................................................................................................................ 12 
Financial considerations  ........................................................................................................................................................................ 12 
Biobank  ................................................................................................................................................................................................. 13 

 
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Law and permits  .................................................................................................................................................................................... 13 
Substitution  ........................................................................................................................................................................................... 13 
Publication ............................................................................................................................................................................................. 13 
Research group  ..................................................................................................................................................................................... 13 
Authorship  ............................................................................................................................................................................................. 13 
Perspective  ........................................................................................................................................................................................... 14 
Study 1:  ........................................................................................................................................................................................ 14 
Study 2:  ........................................................................................................................................................................................ 14 
References  ............................................................................................................................................................................................ 14 
Layman's summary  ........................................................................................................................... Fejl! Bogmærke er ikke defineret. 
 
 
 

 
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BACKGROUND 
Shortness of breath is a frequent symptom and can be caused by many different disorders from several differ-
ent organs. Many patients experience shortness of breath as a result of heart or lung disease or as a compli-
cation of thoracic surgery. Shortness of breath is a subjective sensation and can be caused by a lack of oxygen, 
reduced ventilation or dysfunctional breathing muscles. 
The diaphragm is the main breathing muscle. Decreased ability to contract the diaphragm causes shortness 
of breath. The investigation of dysfunction of the diaphragm is complicated by the fact that newly discovered 
shortness of breath is not specific to diaphragm dysfunction and can be caused by the many other causes of 
shortness of breath. Diaphragm dysfunction is therefore an overlooked cause of shortness of breath. 
We want to shed more light on the function of the diaphragm. Therefore, we will do two studies. The first is a 
method study in which different ultrasound methods are compared with the golden standard, x-ray transillumi-
nation, in healthy, heart- and lung-diseased patients. The second study will assess the diaphragm function in 
patients after thoracic surgery (lung surgery and heart transplantation) and in patients where severe heart 
failure necessitates the need for a mechanical heart heart (Left Ventricular Assist Device, LVAD). 
STUDY 1:  
It is difficult to measure the function of the diaphragm. There are various examination methods to assess the 
function of the diaphragm. Imaging studies, such as x-rays (fluoroscopy) and ultrasound examinations, are 
used. X-ray examination of the chest and diaphragm during breathing is considered an older gold standard, 
but is not really used much in everyday clinical practice. Ultrasound has gradually become the common exam-
ination method, as ultrasound examination allows a number of advantages such as easier use, less set up and 
avoidance of radiation risk. There are several different methods for ultrasound determination of diaphragm 
function, none are sufficiently validated and there is no consensus about the optimal method. There is a need 
for a comparison of different methods with transillumination (golden standard) to establish a precise basis for 
comparison. [1]  
STUDY 2: 
The etiology of shortness of breath is multifactorial, and shortness of breath can be a symptom of a wide range 
of lung or heart diseases. In failing heart pump function, shortness of breath is one of the most frequent symp-
toms. Heart failure can be treated with various types of medicine, but in severe heart failure so that sufficient 
circulation cannot be maintained, heart transplantation may be the only treatment. Shortage of transplant or-
gans results in waiting time for transplantation. Therefore, an LVAD has been developed that can maintain 
adequate blood circulation as either temporary treatment before heart transplantation or as definitive treatment 
in patients who cannot undergo regular heart transplantation. The LVAD is implanted in the thorax and helps 
pump blood from the left ventricle into the aorta. The LVAD is located on top of the left hemidiaphragm and 
can therefore inhibit the movement of the diaphragm. Thereby, the LVAD can give rise to shortness of breath, 
and in patients who have concurrent heart failure, it can thus be difficult to assess whether shortness of breath 
is due to heart failure or reduced diaphragm function. Treatment that these conditions are different. 
Heart transplantation entails a complete replacement of the heart. Due to the close relationship with the phrenic 
nerve, this can be damaged during the operation and thus result in reduced diaphragm function. 
Some diseases, e.g. Cancer of the lung, mediastinum and esophagus requires thoracic surgery. Nerves to the 
diaphragm can be damaged during the operation and thereby cause reduced diaphragm function, which can 
lead to shortness of breath. Pleural effusion is common after thoracic surgery and also manifests as shortness 
of breath. In addition, patients often have other competing diseases such as chronic obstructive pulmonary 

 
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disease (COPD) or heart failure, which can also cause shortness of breath. This results in complex diagnostic 
conditions and complicates the investigation of shortness of breath after thoracic surgery. 
 
 
HYPOTHESIS/AIM 
1. To compare the precision of different ultrasound examination methods for assessing diaphragm func-
tion compared with X-ray translucency. 
2. Investigate whether LVAD implantation, heart transplantation and thoracic surgery affect diaphragm 
function. 
 
TITLES 
1. Precision of sonographic measures of diaphragm function. 
2. The role of diaphragm mobility in heart failure requiring LVAD, heart transplant and thoracic surgery. 
 
METHOD 
DESIGN 
STUDY 1:  
Methodology study. Different ultrasound methods for evaluating diaphragm function are compared with trans-
illumination of the diaphragm. 
STUDY 2:  
Prospective, observational study of diaphragm function before and after thoracic surgery types that may affect 
diaphragm function. 
SETTING 
All studies are carried out at Aarhus University Hospital as a collaboration between Heart Diseases, Lung 
Diseases, Cardiopulmonary and Vascular Surgery, Anesthesia and Surgery and Intensive Care. 
PARTICIPANTS 
STUDY 1:  
Participants are divided into 3 categories: 1/3 healthy, 1/3 lung medicine patients and 1/3 patients who have 
had a heart transplant or LVAD implanted. Everyone over 50 years. 
STUDY 2:  
Patients who must undergo lung surgery or surgery for oesophageal cancer with interventions in the chest 
cavity at Cardiopulmonary and Vascular Surgery as well as patients with severe heart failure who must un-
dergo heart transplantation or LVAD and/or are scheduled for this. 

 
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INCLUSION AND EXCLUSION CRITERIA 
STUDY 1:  
Inclusion criteria: 
o 
Completed informed consent 
o 
1 of the following: 
• 
Quick control person 
• 
Disease in the lungs: COPD or Idiopathic Pulmonary Fibrosis. 
• 
Disease of the heart that has led to a heart transplant or LVAD 
Exclusion criteria: 
o 
Known diaphragm dysfunction 
o 
Neuromuscular disease 
o 
Pleural effusion. Discovered during the investigation 
o 
Pneumothorax. Discovered during the investigation 
o 
Healthy group only (1/3): Significant comorbidity affecting heart or lung function (hypertension and 
mild valvular disease without symptoms is ok), including diagnosed COPD. 
o 
Only healthy group (1/3) and lung disease group (1/3): Previous operation in the thorax 
STUDY 2:  
Inclusion criteria: 
o 
Completed informed consent. 
o 
One of the following: 
• 
Planned LVAD implantation / Heart transplant 
• 
Planned surgery for lung cancer/esophageal cancer. For lung cancer, the planned operation 
must be the removal of one or more lung lobes. 
Exclusion criteria: 
o 
Known diaphragm dysfunction 
o 
Neuromuscular disease 
o 
Pleural effusion (over 1 cm) 
o 
Pneumothorax 
RECRUITMENT 
STUDY 1:  
FAST GROUP:  
Patients who are to be operated on in day surgery at Aarhus University Hospital. In the course of surgery 
(before or after, when patients are awake and capable), patients are informed about the project by a doctor 
associated with the trial. It is ensured that the information can be conveyed in an undisturbed single room. 
Participant information is provided. On the project day (a later date), if there is a desire for this, there will be 
the possibility of a follow-up interview with the possibility of the participation of co-chairs. The reflection time 
will thus be >1 day. Written consent is then secured. Patients have the option of withdrawing consent at any 
time without further requirements for a reason. 

 
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HEART TRANSPLANT RECIPIENTS/LVAD GROUP: 
This patient group is checked with frequent checks after the heart transplant/LVAD. In order to ensure a stable 
phase, all patients who have had a heart transplant and are checked at AUH after 6 months will be invited to 
participate in the present project. The patients will per letter to be informed by a doctor associated with the trial 
about participation. The patients are invited at the next scheduled outpatient visit (as part of the trans-
plant/LVAD check-up) to hear more about the project. It is ensured that the information can be conveyed in an 
undisturbed single room, where oral information is given as well as written information is provided. On the 
project day (a later date), if there is a desire for this, there will be the possibility of a follow-up interview with 
the possibility of the participation of co-chairs. The reflection time will thus be >1 day. Written consent is then 
secured. Patients have the option of withdrawing consent at any time without further requirements for a reason. 
 
 
PULMONARY GROUP: 
Patients who visit the COPD clinic or the Center for Rare Lung Diseases are informed about the project by a 
doctor associated with the trial. It is ensured that the information can be conveyed in an undisturbed single 
room. Participant information is provided. On the project day (a later date), if there is a desire for this, there 
will be the possibility of a follow-up interview with the possibility of the participation of co-chairs. The reflection 
time will thus be >1 day. Written consent is then secured. Patients have the option of withdrawing consent at 
any time without further requirements for a reason. 
  
 
STUDY 2:  
PLANNED HEART TRANSPLANTATION: 
Patients who are registered on the heart transplant list, etc. imminent heart transplant, will be informed about 
the project at the preliminary examination for this treatment or regular check-up prior to heart transplantation, 
which takes place in a private room. Both oral and written information is given here. After being put on the 
waiting list, patients will be informed and written consent will then be secured. Relatively close to this date, 
there will be the possibility of a follow-up interview with the possibility of the participation of co-chairs. The 
reflection time will thus be >1 day. 
Day surgery
Informed by doctor.
Delivery of participant information
Project day
Additional information if desired, with co-owners.
Completing informed consent.
Letter with information
Scheduled outpatient visit
More info.
Delivery of participant 
information
Project day
Additional information if desired, 
with co-owners.
Completing informed consent.
Lung outpatient visit
Informed by doctor.
Delivery of participant information
Project day
Additional information if desired, with co-owners.
Completing informed consent.

 
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PLANNED LVAD: 
Patients who have imminent treatment with an LVAD will be informed about the project during the preliminary 
examination for this treatment, which takes place in a private room. Both oral and written information is given 
here. The day before the operation, when the patients are all already admitted to optimize their cardiac condi-
tion, written consent is secured. On this day, there will be an opportunity for a follow-up interview with the 
possibility of the participation of co-chairs. The reflection time will thus be >1 day. 
 
 
PLANNED SURGERY FOR LUNG CANCER: 
The group that is to be operated on for lung cancer is informed about the project when visiting the Clinic for 
Lung Cancer Investigation. Conversation that takes place in a private room. Written information is provided. 
The day before surgery, when the patients routinely meet for the last interviews before surgery, written consent 
is secured. On these days, there will be the possibility of a follow-up interview with the possibility of the partic-
ipation of co-chairs. The reflection time will thus be > 1 day. 
 
PLANNED SURGERY FOR ESOPHAGEAL CANCER: 
The group that is to be operated on for oesophageal cancer is informed about the project when visiting the 
Cardiopulmonary Surgery Clinic. Conversation that takes place in a private room. Written information is pro-
vided. The day before surgery, when the patients routinely meet for the last interviews before surgery, written 
consent is secured. On these days, there will be the possibility of a follow-up interview with the possibility of 
the participation of co-chairs. The reflection time will thus be > 1 day.  
 
 
SURVEYS 
STUDY 1: 
Registration for a heart transplant:
Informed by doctor.
Delivery of participant information
At least 2 days after the prescription:
Additional information if desired, with co-owners.
Completing informed consent.
LVAD pre-study:
Informed by doctor.
Delivery of participant information
The day before LVAD surgery:
Additional information if desired, with co-owners.
Completing informed consent.
Lung cancer investigation visit:
Informed by doctor.
Delivery of participant information
The day before lung cancer surgery:
Additional information if desired, with co-owners.
Completing informed consent.
Pre-study cardiopulmonary surgery:
Informed by doctor.
Delivery of participant information
The day before esophageal cancer surgery:
Additional information if desired, with co-owners.
Completing informed consent.

 
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In study 1, 1 lung function examination, 1 complete ultrasound examination and 1 x-ray examination are carried 
out. 
STUDY 2: 
In study 2, only lung function examination and ultrasound examination are carried out. These are made 
Lung cancer: 1) the day before surgery, 2) 3 days after surgery and 3) 2 weeks after surgery. 
Oesophageal cancer: 1) the day before surgery, 2) 3 days after surgery and 3) 10 days after surgery (after 
which most are discharged). 
LVAD implantation: 1) the day before surgery, 2) 14 days after surgery and 3) 3 months after surgery. 
Heart transplant: 1) in close relation to the write-up on the heart transplant list, 2) 14 days after the operation 
and 3) 3 months after the operation 
 
PULMONARY FUNCTION TEST: 
Lung function testing takes place by having the patient blow as hard as they can into a tube. Various endpoints 
are then measured automatically by a machine. 3 inhalations are made per study, of which the values from 
the best are used. 
INSPIRATION'S PRINT: 
Inspiratory pressure is measured with an electronic manometer. It consists of a mouthpiece that you breathe 
into and which automatically measures the pressure. 
ULTRASOUND EXAMINATIONS: 
The participants are examined in a standing/sitting position with ultrasound in the mid-axillary line with the 
liver/spleen as a reference point on the right and left side. A movie clip is saved for later analysis. 
Diaphragm movement is measured in 3 different ways: M-mode, Area method and B-mode. [1] [2] [3] [4] Dia-
phragm thickening fraction is measured in 1 way. [5] 
Normal and deep breathing is carried out. 
TRANSLUCENT: 
Performed only in study 1. Film clips of the movement of the diaphragm during X-ray translucency are recorded. 
Transillumination, inspiratory pressure measurement and ultrasound examination are carried out simultane-
ously. Normal and deep breathing is carried out. 
ENDPOINTS 
STUDY 1:  
Diaphragm movement and thickening fraction compared to the cranial movement of the diaphragm as meas-
ured by translucency (gold standard) for the following measures: 
Primary endpoint: 

 
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o 
Movement of the right hemidiaphragm: 1. M-mode method. 
Secondary endpoints 
o 
Movement of the right hemidiaphragm by 1. Area method & 2. B-mode. 
o 
Thickening fraction of the right hemidiaphragm: 1. B-mode. 
o 
Inspiratory pressure 
The above is assessed by correlations and Bland-Altman analysis where relevant. 
Correlations are made between lung function (FEV1, FVC, FRC) and ultrasound measurement of diaphragm 
function (see above) as well as diaphragm function measured by transillumination. 
STUDY 2:  
Change over time of: 
Primary endpoint 
o 
M-mode method of diaphragm movement (ultrasound, only on the right hemidiaphragm). 
Secondary endpoints 
o 
Area method for diaphragm movement (ultrasound and transillumination for LVAD patients). 
o 
B-mode method of diaphragm movement (ultrasound). 
o 
Lung function (FEV1, FVC, FRC). 
STRENGTH CALCULATION 
STUDY 1:  
There is no data available for test-retest variance within ultrasound methods or fluoroscopy. It is therefore 
not possible to make a power calculation of how the spread in the comparison of two methods will be (Limits 
of agreement with Bland-Altman analysis). The starting point is therefore the bias (absolute difference in 
mean value) between an ultrasound method (m-mode method) and transillumination. As this is a methodo-
logical study, greater requirements are set than in study 2 (see below) for which bias can be detected. As-
suming equal variation for the two methods, a detection of bias of 10% (SD 36%, own data for M-mode 
method) will require 92 participants (power 0.8 and alpha 0.05). Due to uncertainty about SD on the screen-
ing method, it is desired to include 100 participants. 
STUDY 2:  
LUNG/OESOPHAGEAL CANCER PATIENTS: 
Data from own research shows diaphragm movement of 6.65mm (SD 2.38) (M-mode method). At a power of 
0.9 and alpha 0.05, 36 patients are needed (before-after situation) to show a 20% change that is considered 
clinically relevant. In order to compensate for drop-outs and an unknown diaphragm movement in particular 
lung surgery patients, it is desired to include 50 patients. 
LVAD/HTX PATIENTS: 
A pragmatic approach is desired. It is desired to include all patients who are operated on with the implantation 
of an LVAD/Heart transplant over 2 years (approx. 40 patients). 

 
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SUMMARY OF DESIRED NUMBER OF INCLUDED PATIENTS 
STUDY 1: 
We want 100 patients (34 healthy, 33 pulmonary medicine patients and 33 patients who have had a heart 
transplant/LVAD) included, distributed equally between the 3 groups to compensate for drop-outs and increase 
power. 
STUDY 2: 
It is desired to include 50 lung/oesophagus patients with the same reasoning as above. Regarding LVAD/heart 
transplant patients, it is desired to include all patients who are recommended for surgery over 2 years (approx. 
40 patients) 
DATA REGISTRATION 
The following demographic data are recorded: sex, height, weight, age and comorbidity. Demographic data is 
obtained from Region Midt's EPR system as well as anamnestic data. Consent to the trial gives the trial group 
and any accounting body the right to obtain information in the patient record regarding conditions that are 
relevant to the trial and for control purposes. 
Data is registered in Case-Report-Form in RedCAP, which is administered by Aarhus University. The Danish 
Data Protection Authority's rules are followed and all personally identifiable data is deleted at the end of the 
study. 
DATA ANALYSIS 
STUDY 1:  
Movement is measured continuously (centimeters or square centimeters) and calculated as a mean with stand-
ard deviation for the various ultrasound measurements. Correlation between diaphragm movement and sex, 
age, BMI is analyzed with multivariable analysis of variance, MANOVA. 
The different measurement methods are compared individually with the golden standard with the paired T-test 
(Wilcocon's test if non-parametric). The 0 hypothesis is that there is no difference between the index method 
and the golden standard. Data is also depicted with a Bland-Altman plot and correlation between the index 
test and the golden standard. 
 
STUDY 2: 
Participants act as their own controls and before/after differences are analyzed with or univariate ANOVA for 
repeated measurements. 
BLINDING 
Analysis of ultrasound films is performed blinded to data for translucency in study 1. 
 
RISKS AND DISADVANTAGES 

 
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STUDY 1 & 2:  
Ultrasound examination, lung function examination and manometry are without risks. 
STUDY 1 ONLY:  
Transillumination with X-rays includes irradiation. Based on an expected radiation time of a maximum of 1 
minute (closer to 30 s), the accumulated radiation dose is estimated to be 0.1-1 mSievert. This would theoret-
ically increase the lifetime risk of developing serious cancer by <0.01%. 
Patients will have to attend the hospital on a day when they would not otherwise have to attend. Participation 
in the experiment takes approx. 30 minutes. 
No compensation or inconvenience allowance will be paid to trial participants. 
 
ETHICAL CONSIDERATIONS 
STUDY 1:  
Ultrasound examinations and lung function examination are without any kind of risks or discomfort for the 
participants and the examinations do not contain any ethical considerations. 
The participants will be X-rayed. The radiation dose is minimal and the expected, accumulated dose of 0.1-
1mSievert must be compared to being exposed to approx. 3 mSv for background radiation annually. The ex-
pected radiation dose corresponds to an increased risk of serious cancer of 1 in 100,000. If it turns out that 
there is good correlation and agreement between ultrasound methods and fluoroscopy, there will be no need 
for fluoroscopy in the future if dysfunction of the diaphragm muscle is suspected, and future patients will there-
fore be spared radiation. [6] It will also be possible to reduce the radiation dose employees are exposed to. In 
study 1, only subjects aged ≥50 years are included in order to minimize the risk of developing cancer second-
ary to the experiment. There have been no studies in which the radiation dose during fluoroscopy is indicated, 
as it depends on the apparatus and method. In this study, we record the total radiation dose, and the total 
radiation dose is closely monitored. 
STUDY 2:  
The ultrasound examinations are performed independently of LVAD implantation or surgery for lung/oesoph-
ageal cancer. The examinations are carried out at already planned clinic visits in order to reduce the burden 
on the patients. 
Overall, we believe that the clinical potential of the study outweighs the risks and disadvantages that the pa-
tients are exposed to. 
 
ECONOMIC CONSIDERATIONS  
The group listed below, all employed at Aarhus University Hospital, has taken the initiative for the experiment. 
All costs for equipment, personnel and utensils are covered by the departments involved and their respective 
research sections, and the experiment has not received any money from outside. None of the researchers 
involved have personal, financial interests in the experiment. 

 
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BIOBANK 
A biobank will not be established 
 
LAW AND PERMITS 
The Act on the processing of personal data will be complied with. 
Studies 1 and 2 require approval from the Scientific Ethics Committee. 
Studies 1 and 2 require approval from the Danish Data Protection Authority. 
Both studies are registered in ClinicalTrials.org. 
Both trials only include the use of CE marked equipment and therefore do not require approval from the Danish 
Medicines Agency. 
 
COMPENSATION 
The trial is covered by the patient reimbursement 
 
PUBLICATION 
Results, positive, negative or inconclusive, are sought to be published in peer-reviewed medical journals. 
Likewise, results will be disseminated at scientific congresses. 
 
RESEARCH GROUP 
Søren Helbo Skaarup, doctor, Lung diseases. Aarhus University Hospital. 
Brian Bridal Løgstrup, senior physician, Heart diseases. Aarhus University Hospital. 
Morten Bendixen, senior physician, Heart, Lung and Vascular Surgery. Aarhus University Hospital. 
Thomas Birkelund, ward physician, Intensive Care Unit. Aarhus University Hospital. 
Peter Juhl-Olsen, department physician, clinical associate professor, Anesthesia and Surgery. Aarhus 
University Hospital. 
 
AUTHORSHIP 
Qualification for authorship requires participation in study design and concept development, data collection, 
data processing, interpretation of data and participation in manuscript writing. All authors must approve the 
manuscript. 
 

 
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PERSPECTIVE 
STUDY 1: 
The first study will identify the optimal research method. This makes it much easier and safer to examine future 
patients, as you want to avoid X-rays. 
STUDY 2: 
The second study will focus on a probably overlooked cause of shortness of breath in patients with severe 
heart failure and in patients undergoing thoracic surgery, which will be able to optimize treatment and avoid 
unnecessary examinations and treatment. 
 
REFERENCES 
1.  
Ferrari G, Helbo Skaarup S, Panero F, et al. The diaphragm. Thorac Ultrasound Sheffield, United 
Kingdom: European Respiratory Society; pp. 129–47. 
2.  
Skaarup SH, Løkke A, Laursen CB. The Area method: a new method for ultrasound assessment of 
diaphragmatic movement. Crit Ultrasound J 2018;10:15. 
3.  
Baria MR, Shahgholi L, Sorenson EJ, et al. B-Mode Ultrasound Assessment of Diaphragm Structure 
and Function in Patients With COPD. Chest 2014;146:680–5. 
4.  
Houston JG, Angus RM, Cowan MD, et al. Ultrasound assessment of normal hemidiaphragmatic 
movement: relation to inspiratory volume. Thorax 1994;49:500–3. 
5.  
Carrillo-Esper R, Perez-Calatayud AA, Arch-Tirado E, et al. Standardization of Sonographic 
Diaphragm Thickness Evaluations in Healthy Volunteers. Respir Care 2016;61:920–4. 
6.  
Guidelines on the use of ionizing radiation in health science experiments. National Scientific Ethics 
Committee. http://www.nvk.dk/~/media/NVK/Dokumenter/Appendiks-2.pdf 
 
 
 

 
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ASSESSMENT OF DIAPHRAGM'S FUNC-
TION. 
A METHODOLOGICAL STUDY AND A CLINI-
CAL STUDY 
Protocol summary 
  
Doctors responsible for the project: 
Søren Helbo Skaarup, doctor, Lung diseases. Aarhus University Hospital. 
Brian Bridal Løgstrup, senior physician, Heart diseases. Aarhus University Hospital. 
Morten Bendixen, senior physician, Heart, Lung and Vascular Surgery. Aarhus University Hospital. 
Thomas Birkelund, ward physician, Intensive Care Unit. Aarhus University Hospital. 
Peter Juhl-Olsen, department physician, clinical associate professor, Anesthesia and Surgery. Aarhus 
University Hospital. 
 
Test site: 
Aarhus University Hospital 
 
 
BACKGROUND & PURPOSE 
We want to do two studies, both of which deal with the function of the diaphragm muscle. 
The diaphragm muscle is the most important muscle for breathing. Poor functioning of the breathing muscle 
causes shortness of breath, but shortness of breath can be caused by many other conditions. It can be dis-
eases of the heart, lungs or following operations in the chest. Furthermore, with the current examination meth-
ods, it is difficult to examine and assess the function of the diaphragm muscle, as there are different ways of 
examining the muscle, of which the established method (X-ray fluoroscopy) is both difficult and associated 
with radiation for both patients and examiners. 
In the first study, we will compare different examination methods to assess the diaphragm muscle. X-rays have 
been used and are considered the best method, perhaps mostly for historical reasons. With an ultrasound 
examination, however, the function of the diaphragm muscle can also be assessed, and ultrasound is com-
pletely risk-free. The connection between X-ray recordings and the various ultrasound examination methods 
has not been investigated. We want to examine a number of healthy people, as well as patients with heart and 
lung diseases. The purpose is to examine exactly how newer ultrasound methods perform compared to the 
classic examination method, X-ray fluoroscopy. 

 
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In the second study, we will investigate changes in the function of the diaphragm muscle in patients undergoing 
surgery in the chest cavity. During surgery in the chest cavity, you get close to and often affect the nerve that 
controls the diaphragm muscle. It is unclear whether this can cause lasting or short-term (days) effects on the 
diaphragm. In the study, the patients' function of the diaphragm muscle is measured before and after surgery. 
The aim is to elucidate the extent to which different types of surgery (lung cancer, oesophageal cancer, heart 
transplantation and insertion of an artificial heart pump (LVAD) affect the function of the diaphragm. 
 
METHOD, DESIGN & RESEARCH METHODS 
 
DESIGN 
STUDY 1: 
Methodology study. Different ultrasound methods for assessing diaphragm function are compared with x-ray 
fluoroscopy. 
STUDY 2: 
Observational study. Patients who are to have surgery in the chest cavity have their lungs scanned with ultra-
sound before and after surgery. 
SETTING 
All studies are carried out at Aarhus University Hospital as a collaboration between Heart Diseases, Lung 
Diseases, Cardiopulmonary and Vascular Surgery, Anesthesia and Surgery and Intensive Care. 
PARTICIPANTS 
STUDY 1: 
Participants are divided into 3 categories: 1/3 healthy, 1/3 lung medicine patients and 1/3 patients who have 
had a heart transplant or LVAD implanted. Everyone over 50 years. 
STUDY 2: 
Patients who must undergo lung surgery or surgery for esophageal cancer with interventions in the chest cavity 
at Heart, Lung and Vascular Surgery, as well as patients with severe heart failure who must undergo heart 
transplantation or LVAD implantation. 
INCLUSION AND EXCLUSION CRITERIA 
STUDY 1: 
Inclusion criteria: 
o 
Completed informed consent 
o 
1 of the following: 
• 
Healthy control person over 50 years of age 
• 
Lung disease: Smoker's lungs or stone lungs 

 
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• 
Disease of the heart that has led to a heart transplant or implantation of an LVAD. 
Exclusion criteria: 
o 
Known dysfunction of the diaphragm 
o 
Chronic nerve or muscle disease 
o 
Fluid in the lung cavity. Discovered during the investigation 
o 
Air in the lung cavity. Discovered during the investigation 
o 
Only group healthy (1/3): Significant disease affecting heart or lung function (high blood pressure and 
mild heart valve disease without symptoms is ok), including diagnosed smoker's lungs. 
o 
Only healthy group (1/3) and lung disease group: 
STUDY 2: 
Inclusion criteria: 
o 
Completed informed consent. 
o 
One of the following: 
• 
Planned LVAD implantation / Heart transplant 
• 
Planned surgery for lung cancer/esophageal cancer 
Exclusion criteria: 
o 
Known dysfunction of the diaphragm 
o 
Chronic nerve or muscle disease 
o 
Fluid in the lung cavity. Discovered during the investigation 
o 
Air in the lung cavity. Discovered during the investigation 
SURVEYS 
STUDY 1: 
In study 1, 1 lung function examination, 1 complete ultrasound examination and 1 x-ray examination are carried 
out. 
STUDY 2: 
In study 2, only lung function examination and ultrasound examination are carried out. These are made 
Lung cancer: 1) the day before surgery, 2) 3 days after surgery and 3) 2 weeks after surgery. 
Oesophageal cancer: 1) the day before surgery, 2) 3 days after surgery and 3) 10 days after surgery (after 
which most are discharged). 
LVAD implantation: 1) the day before surgery, 2) 14 days after surgery and 3) 3 months after surgery. 
Heart transplant: 1) in close relation to the write-up on the heart transplant list, 2) 14 days after the operation 
and 3) 3 months after the operation 
 
PULMONARY FUNCTION TEST: 

 
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Lung function testing takes place by having the patient blow as hard as they can into a tube. Various endpoints 
are then measured automatically by a machine. 3 inhalations are made per study, of which the values from 
the best are used. 
INSPIRATORY PRESSURE: 
 
Inspiratory pressure is measured with an electronic manometer. It is a mouthpiece that you breathe into and 
which automatically measures pressure. 
ULTRASOUND EXAMINATIONS: 
The participants are examined in a standing/sitting position with the liver/spleen as a reference point on the 
right and left side. A movie clip is saved for later analysis. 
Normal and deep breathing is carried out. 
X-RAY REVIEW: 
Only carried out in study 1. Film clips are recorded of the movement of the diaphragm during X-ray translu-
cency. 
RISKS AND DISADVANTAGES 
STUDY 1 & 2: 
Ultrasound examination, lung function examination and manometry are without risks. 
STUDY 1 ONLY: 
Transillumination with X-rays includes irradiation. Based on an expected radiation time of a maximum of 1 
minute (closer to 30 s), the accumulated radiation dose is estimated to be 0.1-1 mSievert. This would theoret-
ically increase the lifetime risk of developing serious cancer by <0.01%. 
Patients will have to attend the hospital on a day when they would not otherwise have to attend. Participation 
in the experiment takes approx. 30 minutes. 
No compensation or inconvenience allowance will be paid to trial participants. 
 
ETHICAL CONSIDERATIONS 
STUDY 1: 
Ultrasound examinations and lung function examination are without any kind of risks or discomfort for the 
participants and the examinations do not contain any ethical considerations. 
The participants will be X-rayed. The radiation dose is minimal and the expected, accumulated dose of 0.1-
1mSievert must be compared to being exposed to approx. 3 mSv for background radiation annually. The ex-
pected radiation dose corresponds to an increased risk of serious cancer of 1 in 100,000. If it turns out that 
there is a good correlation between ultrasound methods and fluoroscopy, there will be no need for fluoroscopy 
in the future if dysfunction of the diaphragm muscle is suspected, and future patients will therefore be spared 

 
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radiation. [6] It will also be possible to reduce the radiation dose employees are exposed to. In study 1, only 
subjects aged ≥50 years are included in order to minimize the risk of developing cancer secondary to the 
experiment, as it takes many years from exposure to radiation to developing cancer. In this study, we record 
the total radiation dose, and the total radiation dose is closely monitored. 
 
STUDY 2: 
The ultrasound examinations are performed independently of LVAD implantation or surgery for lung/oesoph-
ageal cancer. The examinations are carried out at already planned clinic visits in order to reduce the burden 
on the patients. 
Overall, we believe that the clinical potential of the study outweighs the risks and disadvantages that the pa-
tients are exposed to. 
ECONOMIC CONSIDERATIONS 
The group listed below, all employed at Aarhus University Hospital, has taken the initiative for the trial. All costs 
for equipment, personnel and utensils are covered by the departments involved and their respective research 
sections, and the experiment has not received any money from outside. None of the researchers involved have 
personal, financial interests in the experiment. 
 
BIOBANK 
A biobank will not be established 
 
RECRUITMENT 
STUDY 1: 
FAST GROUP:  
Patients who are to be operated on in day surgery at Aarhus University Hospital. In the course of surgery 
(before or after, when patients are awake and capable), patients are informed about the project by a doctor 
associated with the trial. It is ensured that the information can be conveyed in an undisturbed single room. 
Participant information is provided. On the project day (a later date), if there is a desire for this, there will be 
the possibility of a follow-up interview with the possibility of the participation of co-chairs. The reflection time 
will thus be >1 day. Written consent is then secured. Patients have the option of withdrawing consent at any 
time without further requirements for a reason. 
 
 
HEART TRANSPLANT RECIPIENTS/LVAD GROUP: 
Day surgery
Informed by doctor.
Delivery of participant information
Project day
Additional information if desired, with co-owners.
Completing informed consent.

 
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This patient group is checked with frequent checks after the heart transplant/LVAD. In order to ensure a stable 
phase, all patients who have had a heart transplant and are checked at AUH after 6 months will be invited to 
participate in the present project. The patients will per letter to be informed by a doctor associated with the trial 
about participation. The patients are invited at the next scheduled outpatient visit (as part of the trans-
plant/LVAD check-up) to hear more about the project. It is ensured that the information can be conveyed in an 
undisturbed single room, where oral information is given as well as written information is provided. On the 
project day (a later date), if there is a desire for this, there will be the possibility of a follow-up interview with 
the possibility of the participation of bystanders. The reflection time will thus be >1 day. Written consent is then 
secured. Patients have the option of withdrawing consent at any time without further requirements for a reason. 
 
 
PULMONARY GROUP: 
Patients who visit the COPD clinic or the Center for Rare Lung Diseases are informed about the project by a 
doctor associated with the trial. It is ensured that the information can be conveyed in an undisturbed single 
room. Participant information is provided. On the project day (a later date), if there is a desire for this, there 
will be the possibility of a follow-up interview with the possibility of the participation of co-chairs. The reflection 
time will thus be >1 day. Written consent is then secured. Patients have the option of withdrawing consent at 
any time without further requirements for a reason. 
  
 
STUDY 2: 
PLANNED HEART TRANSPLANTATION: 
Patients who are registered on the heart transplant list, etc. imminent heart transplant, will be informed about 
the project at the preliminary examination for this treatment or regular check-up prior to heart transplantation, 
which takes place in a private room. Both oral and written information is given here. After being put on the 
waiting list, patients will be informed and written consent will then be secured. Relatively close to this date, 
there will be the possibility of a follow-up interview with the possibility of the participation of co-chairs. The 
reflection time will thus be >1 day. 
 
 
 
PLANNED LVAD: 
Letter with information
Scheduled outpatient visit
More info.
Delivery of participant 
information
Project day
Additional information if desired, 
with co-owners.
Completing informed consent.
Lung outpatient visit
Informed by doctor.
Delivery of participant information
Project day
Additional information if desired, with co-owners.
Completing informed consent.
Registration for a heart transplant:
Informed by doctor.
Delivery of participant information
At least 2 days after the prescription:
Additional information if desired, with co-owners.
Completing informed consent.

 
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Patients who have imminent treatment with an LVAD will be informed about the project during the preliminary 
examination for this treatment, which takes place in a private room. Both oral and written information is given 
here. The day before the operation, when the patients are all already admitted to optimize their cardiac condi-
tion, written consent is secured. On this day, there will be an opportunity for a follow-up interview with the 
possibility of the participation of co-chairs. The reflection time will thus be >1 day. 
 
 
PLANNED SURGERY FOR LUNG CANCER: 
The group that is to be operated on for lung cancer is informed about the project when visiting the Clinic for 
Lung Cancer Investigation. Conversation that takes place in a private room. Written information is provided. 
The day before surgery, when the patients routinely meet for the last interviews before surgery, written consent 
is secured. On these days, there will be the possibility of a follow-up interview with the possibility of the partic-
ipation of co-chairs. The reflection time will thus be > 1 day. 
 
PLANNED SURGERY FOR ESOPHAGEAL CANCER: 
The group that is to be operated on for oesophageal cancer is informed about the project when visiting the 
Cardiopulmonary Surgery Clinic. Conversation that takes place in a private room. Written information is pro-
vided. The day before surgery, when the patients routinely meet for the last interviews before surgery, written 
consent is secured. On these days, there will be the possibility of a follow-up interview with the possibility of 
the participation of co-chairs. The reflection time will thus be > 1 day.  
 
 
PUBLICATION 
Results, positive, negative or inconclusive, are sought to be published in an international journal. Likewise, 
results will be disseminated at scientific congresses. 
 
 
LVAD pre-study:
Informed by doctor.
Delivery of participant information
The day before LVAD surgery:
Additional information if desired, with co-owners.
Completing informed consent.
Lung cancer investigation visit:
Informed by doctor.
Delivery of participant information
The day before lung cancer surgery:
Additional information if desired, with co-owners.
Completing informed consent.
Pre-study cardiopulmonary surgery:
Informed by doctor.
Delivery of participant information
The day before esophageal cancer surgery:
Additional information if desired, with co-owners.
Completing informed consent.