Monitorings the Physiological Mechanism of Airway Pressure Release Ventilation(APRV) in Acute Respiratory Distress Syndrome (ARDS) Patients by Electrical Impedance Tomography(EIT)
Conditions: Electrical Impedance Tomography, ARDS
Sponsor: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

 
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Project name: Using electrical impedance tomography to monitor the 
effect of airway pressure release ventilation on the respiratory mechanism 
of acute respiratory distress syndrome 
NCT number: NO 
Unique Protocol ID: TTEC20220103 
Investigator Name: Xiaojing Zou，MD  
Investigator Affiliation: Wuhan Union Hospital, China 
Sponsor: Wuhan Union Hospital, China 
Collaborators: No 
Email: 
249126734@qq.com 
Time Frame: March 1, 2022 -- March 1, 2024 
      Date of this document: February 08, 2022  
 
 
 
 
 
 
 
 
 
 

 
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1. Introduction 
1.1 Background  
1.1.1 Basic introduction 
Acute respiratory distress syndrome(ARDS) is common syndrome in 
ICU which is characteristic by diffuse endothelial cell and epithelial 
damage,inflammatory edema,heterogeneous lung injury and refractory 
hyoxemia.Mechanical ventilation(MV) is the major treatment for 
ARDS.Lung 
protective 
MV 
including 
low 
tidal 
volume 
(LTV),appropriate positive end expiratory pressure(PEEP) and prone 
position ventilation(PPV) has been proved to improve outcome 
effectively. Despite these measures, the mortality of ARDS is still high, 
up to 30-50%. 
Airway pressure release ventilation(APRV) is an kind of inverse 
ratio ventilation that provides consistently high mean airway pressure 
(mPaw) which preventing alveolar collapse/hyperventilation and 
recurrent opening/closure theoretically. Clinical trials have shown it to be 
effective to improve oxygenation and lung compliance in ARDS 
patients.Animal studies have also shown that compared with low tidal 
volume ventilation,APRV could improve oxygenation, reduce lung 
heterogeneity and alveolar over-expansion, reduce lung inflammation and 
histopathological damage.However, the ventilatory and blood flow 
changes on local lung tissues of ARDS patients during APRV have not 

 
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been confirmed.Moreover, due to the lung heterogeneity in ARDS 
patients, the increase of mPaw may lead to local lung  over-expanded 
and collapsed simultaneously, which may result in the increase of  
pulmonry shunt fraction and dead space ventilation.Therefore, bedside 
monitoring of physiological effects of APRV in ARDS patients’ lung 
would help to better understand the efficacy of APRV in clinical 
application. 
Electrical impedance tomography (EIT) is a noninvasive, 
nonradiological, real-time bedside lung imaging technology which can 
monitoring local alveolar over-expansion and collapse.In recent years, 
EIT has been proposed to assess pulmonary perfusion by injecting 
saline.Therefore, EIT would be an ideal bedside tool to evaluate the 
effects of APRV on respiratory physiology. We hypothesized that EIT 
may help to clarify the effects of APRV on local lung ventilation, 
pulmonary shunt,dead space ventilation and V/Q ratio.  
1.1.2 Preliminary Research Basis 
In animal models of ARDS, APRV was found to reduce 
ventilation-induced 
lung 
injury 
(VILI) 
and 
improve 
alveolar 
heterogeneity. 
RCT studies showed that compared with LTV, APRV improved 
oxygenation and lung compliance, and reduced duration of mechanical 
ventilation in ARDS patients significantly. 

 
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1.2 Study type 
A single-center prospective observational study. 
1.3 Study basis 
ARDS is an acute, diffuse, inflammatory lung injury that results in 
increased alveolar capillary permeability and lung weight, and loss of 
aerated lung tissue.Current guidelines for ARDS include LTV for lung 
protective ventilation to improve oxygenation, which is recommended to 
all types of ARDS patients.However, the lung injury of ARDS is 
"heterogeneous", with alveolar collapse and atelectasis in gravity 
dependent area and over-expansion non-gravity dependent area. Besides, 
due to the geometric effects, parenchyma at the boundary between 
unidirectional and aerated parenchyma may bear greater strain and 
stress.APRV is an kind of inverse ratio ventilation that provides 
consistently high mean airway pressure (mPaw) to prevent alveolar 
collapse/hyperventilation and recurrent opening/closure theoretically. 
Clinical trials showed that APRV can improve oxygenation and lung 
compliance 
effectively, 
and 
reduce 
mechanical 
ventilation 
duration.Animal models of ARDS also showed that compared with LTV, 
APRV can improve oxygenation and reduce pulmonary heterogeneity and 
alveolar over-expansion, reduce lung inflammation and histopathological 
damage.However, up to now,the changes of ventilatory and blood flow in 
local lung tissue of ARDS patients during APRV have not been studied.In 

 
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addition, due to the high degree of respiratory heterogeneity in ARDS 
patients, the increase of mPaw may lead to simultaneous hyperexpansion 
and collapse of local lung tissues, which may be followed by an increase 
in pulmonary shunt fraction and dead space ventilation.Bedside 
monitoring of the physiological effects of APRV on the lungs would help 
to better understand the efficacy of APRV in clinical practice. EIT is a 
noninvasive,nonradioactive real-time bedside lung imaging tool for 
monitoring local alveolar over-expansion and collapse.In addition, EIT 
can be used to assess the V/Q ratio by injecting saline, contributing to a 
deeper understanding of the respiratory physiology of APRV on local 
lung tissues. 
1.4 Risk and benefit 
1.4.1 Known potential risks 
Several animal experiments and clinical studies have demonstrated 
that APRV can effectively improve oxygenation and reduce MV duration. 
Compared with conventional MV, APRV is relatively safe. Therefore, 
there is no potential risk in this study. 
1.4.2 Probability of injury 
Mechanical ventilation is a routine treatment for patients with 
respiratory failure in the ICU, and its safety is well established. 
1.4.3 Degree of injury 
The subjects will suffer very minor injuries and have no fatal 

 
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adverse events. 
1.4.4 Known potential benefits 
MV is a routine treatment for ARDS patients. Compared with LTV, 
APRV ventilation can effectively improve oxygenation and reduce the 
duration of MV in ARDS patients.However, since APRV was classified as  
inverse ratio ventilation and relatively complex, it has not been widely 
applied in clinical practice. In this research, we will clarify the effect of 
APRV on pulmonary respiration mechanism in ARDS patients by EIT 
monitoring, and provide more clinical evidence for the application of 
APRV in ARDS patients. 
1.4.5 Assessment of potential risks/benefits 
MV is a routine treatment for ARDS patients. APRV is a classical 
mode of MV that has been used in the treatment for ARDS patients over 
20 years. Animal and clinical studies have shown that it can effectively 
improve oxygenation, reduce the duration of MV and the length of ICU 
stay with less complications. However, due to the uncertainty of  
mechanism, Its application is still limited in clinical practice. We hope to 
further explore the mechanism of APRV through this study and provide 
sufficient evidence for its clinical promotion in ARDS patients.The 
potential risks of APRV are similar to those of other MV modes. It is a 
life-saving treatment for ARDS patients with minimal risks when 
conducted in appropriate indications and contraindications. 

 
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1.4.6 Discussion 
APRV is a classical mode of MV that can effectively improve 
oxygenation in ARDS patients. Its unique characteristic of inverse radio 
ventilation helps to increase the time of alveolar gas exchange and 
effectively improve oxygenation. In addition, it can increase the mean 
airway pressure to promote the reaeration of collapsed alveoli. Because 
the airway pressure is set according to the platform pressure, there is less 
possibility of barotrauma during APRV. 
At present, the effects of APRV on respiratory physiology are mostly 
limited to animal experimental models of ARDS, and its effects on 
respiratory physiology of ARDS patients still uncertain.For instance, 
whether it can improve the heterogeneity of lung lesions, or promote the 
reaeration of collapsed alveoli, or improve V/Q ratio in ARDS patients 
have not been supported by sufficient clinical evidence.EIT is a 
noninvasive,nonradioactive real-time bedside lung imaging tool for 
monitoring local alveolar.We hypothesized that EIT may help to clarify 
the effects of APRV on local lung ventilation, pulmonary shunt,dead 
space ventilation and V/Q ratio. We hope that this study will help 
clinicians to obtain a deeper understanding of APRV and promote its 
application in ARDS patients. 
2. Objective and outcome 
Objective: to clarify the effect of APRV on pulmonary ventilation 

 
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distribution and V/Q ratio in ARDS patients. 
Primary outcome: Effect of 24h APRV on pulmonary ventilation 
distribution in ARDS patients. 
Secondary outcome: Effects of APRV on lung ventilation distribution and 
V/Q ratio in ARDS patients at different times. 
3. Study design 
3.1 overall design 
A Single center prospective observational study. 
ARDS patients who received APRV were monitored by EIT at the 
time of before APRV and after APRV at 2h, 6h,12h,24h,48h and 72h. MV 
parameters, respiratory mechanics, results of arterial blood gas analysis, 
and hemodynamic status were recorded, and cardiac status was monitored 
by point-of care ultrasound. 
Data collecting 
(1) Demographic data:Sex, age, height, weight. 
(2) Vital signs: Organ function including sequential organ function score 
(SOFA) score,acute physiology and chronic health evaluation Ⅱ 
(APACHEⅡ) score. 
(3) physiological and laboratory test: Blood routine, Serum biochemical 
examination (total protein, albumin (ALB),total bilirubin (TB),aspartate 
aminotransferase (AST), alanine transaminase (ALT), gamma-glutamyl 
transpeptidase (GGT),blood urea nitrogen (BUN), serum creatinine (Scr)), 

 
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brain natriuretic peptide (BNP), C-reactive protein (CRP), respiratory 
mechanics, cardiac and hemodynamic status at the time of before APRV, 
APRV 24h, ARPV 48h and APRV 72h. 
3.2 sample size 
Referring to previous literatures, the number of patients is generally 
required to be 20, and the number of patients should be increased to 30 in 
consideration of shedding and withdrawal. 
4. Study population 
4.1 Diagnostic criteria 
 ARDS is diagnosed according to the 2014 Berlin definition. 
4.2 Inclusion criteria 
The following three items must be met simultaneously: 
(1) Age: ＞18 years old and ＜80 years old 
(2) ARDS was diagnosed as moderate to severe according to the 2014 
Berlin definition. 
(3) APRV duration is expected to exceed 72 hours. 
4.3 Exclusion criteria 
Any of the following exclusion criteria is an exclusion: 
(1) APRV contraindications including pneumothorax, severe COPD, 
severe asthma, and intracranial hypertension 
(2) Pregnancy and perinatal stage 
(3) Severe cardiac dysfunction (NYHA classⅢor IV, acute coronary 

 
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syndrome 
or 
persistent 
ventricular 
tachyarrhythmia),chronic 
cardiopulmonary disease resulting in enlargement of the right heart, 
cardiogenic shock or cardiac perioperative period 
(4) Refractory shock 
(5) BMI>35 kg/m2 
5. The items and frequency of clinical and laboratory examinations 
to be performed 
Pulmonary gas distribution, pulmonary shunt, and V/Q ratio were 
monitored by EIT before APRV and 2h,6h,12h,24h,48h and 72h after 
APRV. Blood routine, serum biochemistry test,BNP,CRP and arterial 
blood gas were recorded before APRV and 24h,48h and 72h after APRV. 
cardiac status was monitored by point-of-care ultrasound. 
6. Evaluation  
6.1 Primary and secondary outcome 
Primary outcome: the effect of 24h APRV on pulmonary gas distribution 
monitored by EIT. 
Secondary outcome: the effect of APRV on V/Q and pulmonary shunt at 
each time point monitored by EIT. 
6.2 Safety evaluation 
APRV is a mode of MV for ARDS patients and has been shown to be safe 
in animal and clinical studies. 
7. Adverse events and severe adverse events 

 
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Adverse event reports: Adverse medical events that occur in patients 
receiving APRV, but are not necessarily causally related to treatment. 
Reports of serious adverse events: patients receiving APRV  
experienced events requiring prolonged hospitalization, disability, 
incapacity to work, life-threatening events or death. 
During a clinical trial, the clinical investigators are obligated to take 
necessary measures to ensure the safety of the patients and to document 
them timely.If serious adverse events occur during the clinical trial, the 
investigators should immediately administer appropriate treatment to the 
subject, and investigators should report to clinical trial unit Ethics 
committee,provincial or regional food and drug administration and state 
food and drug administration and sponsor by telephone or fax within 24 
hours.At the same time, a written report shall be submitted to the above 
institutions within 15 days.The serious adverse event that occurred during 
study must be completed serious adverse event report form on the CRF. 
All serious adverse events should be followed up until resolved and 
returned to baseline.Medical documentation of serious adverse events that 
proved to be irresolvable/permanent conversion to other treatment or 
death should be documented in the original documentation and follow-up 
form as well as results of laboratory and other tests. 
The investigators and other responsible persons should analyze and 
determine the causal relationship between serious adverse events in the 

 
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subjects from a clinical perspective. 
8. Statistical analysis and methods 
Statistical analysis was performed by Prism 4.01. Due to the 
parameters are abnormal distributed, the data is showed as median 
(interquartile range).The data obtained at each step were compared using 
Friedman ANOVA of repeated measurements and, when appropriate, 
through Dunn post hoc tests using Bonferroni correction.Qualitative data 
were compared with Fisher's exact test.All comparisons were two-sided,P
＜0.05 indicates the existence of significant difference. 
9. Medical treatment and protection of subjects 
9.1 Risk assessment of subjects in the study and risk disposal plan 
(1) Reporting methods: Any adverse events, such as subjects' subjective 
discomfort and abnormal laboratory testing, should be treated seriously 
and analyzed carefully, and immediate measures should be taken to 
protect the safety of subjects 
(2) Processing procedures: detailed records, and according to the situation 
of retest, record the disappearance of its continuous turnaround and other 
circumstances. 
(3) Follow-up for unmitigated adverse events. All adverse events should 
be followed up until they are properly resolved or the disease is stable. 
9.2 Medical treatment and protection of subjects during the study 
The rights and welfare of the subjects will be protected during the 

 
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study, and the quality of their medical care will not be affected by their 
refusal to participate or withdrawal from the study. 
If the patient drops out of the study, we will no longer conduct study 
related tests. 
The investigators will provide insurance for the subjects 
participating in the study program. If the subjects suffer any damage 
related to the study, they will receive timely free treatment and be 
compensated or compensated according to laws and regulations and 
mutual agreements. 
9.3 Medical treatment and protection of subjects after study 
APRV was administered in a investigational manner during the study, 
with inclusion/exclusion criteria clarified and efficacy and safety 
information recorded.Routine treatment was continued after the 
study.Subjects shall not be required to waive their right to free treatment 
and compensation for study related damages. 
10. Supporting documents and notes 
10.1 Informed consent process 
Informed consent was completed before the subjects' relatives 
agreed to participate in the study and continued throughout the 
study.Informed consent was approved by the ETHICS committee, and the 
relatives 
of 
the 
study 
subjects 
should 
read 
the 
informed 
consent.Researchers explain the process and answer questions from 

 
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relatives; The subjects were also informed of possible risks to their 
relatives and their rights. 
The investigator must inform the relatives that their participation is 
voluntary and that they may withdraw from the study at any time during 
the study.Copies of the informed consent can be provided to the relatives 
of the subjects for preservation.The rights and welfare of relatives will be 
protected and it is stressed that the quality of their medical care will not 
be affected by their refusal to participate. 
10.2 privacy protection 
The relevant data of the research object shall be kept by the project 
quality controller, who shall store the relevant form records and samples. 
All investigators should subject to the principle of confidentiality and 
relevant regulations, the ethics committee of the supervisor and the 
inspectors of the drug regulatory department may access the original 
medical records.No research information should be disclosed to 
unauthorized third parties without prior approval. 
10.3 Collection and use of specimens and data 
The blood samples collected by the institute are only used for 
routine medical tests in the treatment process, so there will be no residual 
specimens retained. 
After the study, the retained image data and other data will be used 
for future research with the consent of the subjects. 

 
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10.4 Quality control and quality assurance 
All physicians participating in this study were familiarized with 
APRV mechanical ventilation mode,EIT, and point-of-care ultrasound. 
All physicians participating in this study should be aware of the time 
nodes for testing and blood collection. 
The CRF form should be checked by two persons. 
The project quality control leader shall conduct quality control on 
the study data every week to ensure the safety, accuracy and orderly 
progress of the test. 
10.5 Data processing and record keeping 
10.5.1 Data collection and management 
The required data were collected from the medical records of 
patients who met the inclusion criteria and filled in the paper CRF. 
Data collection will be conducted by the clinical investigator under 
the supervision of the superintendent, who will be responsible for the 
accuracy, completeness and timeliness of the reported data.All data shall 
be clear to ensure accurate interpretation and traceability. 
Data entry: Remote data entry is carried out after the training of data 
entry staff, which is completed by two people independently by using the 
double-copy entry method. 
Data review: Manual comparison of data in the case report form and 
the database to ensure that the data in the database are consistent with the 

 
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results in the CRF. 
Data locking: In addition to the above data review, the principal 
investigator, statistician, data manager and sponsor representative shall 
further discuss and confirm the main content of the research proposal and 
the statistical analysis proposal. Investigator should audit to confirm that 
all data have been entered into the database, all questions have been 
resolved, and the analysis group has been defined and made a judgment 
before locking the data. 
Clinical data will be stored in a database, which shall be password 
protected and logical collation procedures shall be set up when the 
database is established. 
10.5.2 Research data retention 
Specify minimum retention time for all data, original documents, 
and permission to be obtained prior to destruction. 
10.5.3 Statement of conflict of interest 
There is no conflict of interest between this study and any physician 
participating in this clinical study.