Expiratory Muscle Function in Critically Ill Ventilated Patients
Conditions: Mechanical Ventilation, Expiratory Muscle, Critical Illness, Muscle Atrophy or Weakness, Diaphragm
Sponsor: Amsterdam UMC, location VUmc

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Expiratory muscle function in critically ill 
ventilated  patients 
 
 
 
 
NTC:     
Date of approved by METC: February 14, 2017  
Date of amendement approved by METC: May 22, 2019  
 
 
 

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Rationale 
Inspiratory muscle weakness develops rapidly in 
ventilated critically ill patients1-4 and is associated with 
adverse outcome, including prolonged duration of 
mechanical ventilation and mortality.5-7 Surprisingly, the 
effects of critical illness on expiratory muscle function 
have not been studied.  
        The main expiratory muscles are the abdominal 
wall muscles, including the external oblique (EO), 
internal oblique (IO) and transversus abdominis muscles 
(TRA).8,9  These muscles are activated when respiratory 
drive or load increases, which can be during e.g. 
exercise,10-12 diaphragm fatigue,13 increased airway 
resistance, or positive airway pressure ventilation.14 The 
abdominal wall muscles are also critical for protective 
reflexes, such as coughing.15 Reduced abdominal 
muscles strength may lead to decreased cough function 
16,17 and thus inadequate airway clearance.18 This will 
lead to secretion pooling in the lower airways, 
atelectasis, and ventilator associated pneumonia 
(VAP).19,20 Studies have shown that decreased cough 
function is a risk for weaning failure and 
(re)hospitalization for respiratory complications.21  
Further, high mortality was found in patients with low 
peak expiratory flow.22  
        Considering the importance of a proper expiratory 
muscle function in critically ill patients, it is surprising 
that the prevalence, causes, and functional impact of 
changes in expiratory abdominal muscles thickness 
during mechanical ventilation (MV) for critically ill 
patients are still unknown. 

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        Ultrasound is increasingly used in the ICU for the 
visualization of respiratory muscles. In a recent pilot 
study we confirmed the feasibility and reliability of 
using of ultrasound to evaluate both diaphragm and 
expiratory abdominal muscle thickness in ventilated 
critically ill patients (manuscript in preparation). An 
example of such measurement can be found in figure 1. 
Accordingly, the primary aim of the present study is to 
evaluate the evolution of abdominal expiratory muscle 
thickness during MV in adult critically ill patients, using 
ultrasound data. 
 
 
Figure 1. Left: ultrasound of the abdominal expiratory 
muscles (EO, IO, TRA). Right: anatomical overview of the 
abdominal muscles. RA = rectus abdominis, less 
involved in respiration 
Objective 
Primary objective: to establish the effects of critical 
illness and mechanical ventilation on thickness of the 
abdominal expiratory muscles. 
Secondary objectives:  
- to establish the effect of changes in abdominal 
expiratory muscle thickness on the expiratory muscle 
function.   

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- to establish the correlation between changes in 
thickness of the abdominal expiratory and inspiratory 
muscles.  
- to study whether changes in the thickness of the 
abdominal expiratory muscles also affects weaning 
outcome, and ICU readmission due to respiratory 
complications. 
Study design 
Prospective cohort study. 
Study population 
Patients who have been mechanically ventilated at the 
intensive care unit (ICU)  
Inclusive criteria 
- Age > 18 years 
- Invasive mechanical ventilation < 48 hours  
- Expected duration of mechanical ventilation > 72 
hours 
Exclusive criteria 
- Past medical history of neuromuscular disorders 
- Mechanical ventilation > 48 hours within the current 
hospital admission  
- BMI > 35 kg/m2 
- Pregnant women 
- Open abdominal wounds at proposed location of the 
ultrasound probe, due to recent abdominal surgery 
Sample size 
100 subjects  
Recruiting subjects 
Because mechanical ventilation is a requirement for 
eligibility, the participants frequently will be incapable 
of consent at the time of inclusion. Therefore, we will 
ask delayed informed consent from the patient as soon 
as he/she is capable of providing consent. 
If patients are not able to give consent during their 
hospital stay, we will send an opt-out letter to the 
patient.  
 

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Intervention 
Data from ultrasound measurements and from the 
electronic patient record will be obtained / analyzed. 
One additional blood sample will be obtained within 24 
hours after inclusion, during planned blood collection 
(from arterial line or venous puncture). 
Study eindpoint 
- Thickness of the abdominal expiratory muscles 
(external oblique, internal oblique, transverse 
abdominis muscle), during the inspiratory and 
expiratory phases of breathing. 
Study parameters 
- Thickness of the diaphragm muscle 
- Inflammatory markers (TNF-alpha, IL-6, IL-10) at 
inclusion (measured from blood sample using ELISA 
technique). 
- Respiratory function parameters: maximum inspiratory 
pressure (MIP), maximum expiratory pressure (MEP), 
cough peak flow (CPF), diaphragm pressure and 
diaphragm electrical activity (in selected patients with 
these measurements available in clinical practice). 
- Mechanical ventilation parameters. 
- Weaning outcome 
- Ventilator associated pneumonia (VAP) 
- Follow-up of 6 weeks: readmission to ICU / hospital, 
reason for readmission, pneumonia acquired after 
discharge when subject is hospitalized. 
- Critical illness parameters (e.g. medication, APACHE II 
score) 
- Patient characteristics (e.g. gender, age, neurological 
and cardiopulmonary co-morbidities, BMI) 
This data will be retrieved from the electronic patient 
record and anonymously filed in a database.  
Data on muscle thickness (thickness of diaphragm 
muscle and expiratory muscles) will be collected directly 

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from ultrasound measurements on the ultrasound 
device. 
Statistical Analysis 
Plan 
SPSS statistical software package version 22.0 or R 
software for statistical computing version 3.2.0 will be 
used.  
 
Primary endpoint: change of thickness of expiratory 
abdominal muscles during MV. Change in thickness will 
be presented as ratio change compared to baseline, to 
account for inter-subject variation in baseline thickness. 
The Wilcoxon signed-rank test will be used to compare 
changes in baseline and nadir values. 
Association of categorical independent variables (such 
as sex, use of corticosteroids during ICU stay, sepsis on 
admission, etc.) with nadir change in expiratory muscle 
thickness will be assessed using a Mann-Whitney U test. 
Association of continuous independent variables (such 
as duration of mechanical ventilation, days taken to 
wean, inflammation at inclusion, etc.) with nadir change 
in expiratory muscle thickness will be assessed using a 
linear regression model, with change in expiratory 
muscle thickness as dependent variable. Correlation 
between change in thickness during the acute stage of 
MV (5 days) with the total time spent on the ventilator 
will be examined using a linear regression model. 
 
Correlation between diaphragm and expiratory 
muscles 
Correlation between change in expiratory muscle 
thickness and change in diaphragm thickness will be 
assessed with Pearson’s correlation test to compare 
population means. The difference between change in 

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expiratory muscle thickness and change in diaphragm 
thickness will be assessed with a Student’s t-test that is 
paired per subject. This will be done by using the 
change in thickness between baseline and the last data 
point obtained. Second, this will be evaluated by using 
the slope of the thickness curves assessed with a 
goodness of fit model. We will use a goodness of fit 
model to first describe the course of both diaphragm 
and expiratory muscle thickness for each subject. The 
type of model will be determined after data is obtained.  
 
Subgroup analysis 
Based on the outcomes of these analyses, a subgroup 
analysis may be performed to compare the subjects 
with high change in expiratory muscle thickness, to a 
group with low change in expiratory muscle thickness. 
A cutoff value to divide these groups will be determined 
based on how data will emerge. Variables as respiratory 
function measurements can be compared between 
groups with a Student’s t-test, using group average 
values. Further, a Kaplan-Meier survival analysis will be 
carried out to quantify differences in time to wean 
between groups. 
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