Effect of Airway Pressure Release Ventilation(APRV) on Right Ventricular Function Assessed by Transthoracic Echocardiography
Conditions: Ventilation Therapy; Complications, Right Ventricular Function, ARDS, Transthoracic Echocardiography
Sponsor: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

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Project name: The Effect of APRV on Right Ventricular
Function Assessed by Transthoracic Echocardiography
NCT number: NO
Unique Protocol ID: TTEC20220103
Investigator Name: Xiaojing Zou
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
1.The introduction
1.1 Research Background

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1.1.1 Basic Overview
Acute Respiratory Distress Syndrome (ARDS) often complicated with Right
Ventricular Dysfunction (RVD), the incidence of which can be as high as 64%.
Acute cor pulmonale is the most serious form of ARDS complicated with
RVD.The mechanisms include pulmonary vascular dysfunction and right
ventricular systolic dysfunction.Excessive inflammation, hypoxic pulmonary
vasoconstriction, hypercapnia, elevated pulmonary vascular resistance due to
hyperventilation or pulmonary collapse, pulmonary capillary microthrombosis and
pulmonary vascular remodeling are important factors leading to right heart
dysfunction in ARDS.RVD often leads to low cardiac displacement and
hemodynamic failure in patients[1].ARDS patients with RVD have a worse
prognosis and a significantly higher risk of death, which is an independent risk
factor for death in ARDS patients[2-4].
Mechanical ventilation is an important treatment for moderate/ severe
ARDS.Mechanical ventilation has a significant effect on hemodynamics by
affecting the right ventricle by increasing intrathoracic positive pressure.On the
one hand, periodic (moist respiration) or continuous (PEEP application) changes in
transpulmonary pressure caused by respiratory support directly affect the right
ventricular outflow impedance.On the other hand, increased intrathoracic pressure
caused by respiratory support can limit right ventricular diastole.In addition, during
mechanical ventilation, alveolar pressure will directly act on the outside of pulmonary
capillary bed. If alveolar pressure exceeds venous pressure, pulmonary blood flow will be
obstructed.Therefore, mechanical ventilation may significantly increase the right cardiac afterload
by increasing intrathoracic or alveolar pressure, resulting in right cardiac dysfunction and
hemodynamicdisorders[5].
APRV is an inversely proportional mechanical ventilation mode with
transient pressure release under continuous positive airway pressure.
Studies have shown that APRV can improve oxygenation and is very safe
compared with lung protective ventilation with low tidal volume [6]. It is worth

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noting that randomized controlled studies have shown that APRV can increase
average airway pressure compared with low tidal volume ventilation [7], which may
theoretically
increase
intrathoracic
and
alveolar
pressure,
increase
external
pericardium
pressure,
thereby
affecting
venous
return,
increasing
pulmonary
circulation resistance, and leading to right heart dysfunction and even hemodynamic
deterioration.However, the actual effect of APRV on right heart function in ARDS
patients has not been reported.In this study, transthoracic cardiac ultrasound was used to
evaluate right heart function, pulmonary artery pressure, tricuspid regurgitation and
hemodynamics related indicators in ARDS patients receiving APRV mechanical ventilation,
so as to fully understand the influence of APRV mechanical ventilation mode on right heart
function and hemodynamics, which is more conducive to clinical application and avoid the
occurrence of adverse reactions.
1.1.2 Research Types
Prospective single-center observational study
1.1.3 Research Basis
ARDS is often complicated with RVD, and the incidence can be as high as
64%.ARDS patients with RVD have a worse prognosis and a significantly higher
risk of death, which is an independent risk factor for death in ARDS
patients.Randomized controlled studies have shown that compared with low tidal
volume ventilation, APRV can increase average airway pressure [7], which may
theoretically increase intrathoracic pressure and extrapericardial pressure, thereby
affecting venous return, increasing pulmonary circulation resistance, leading to
right heart dysfunction and even hemodynamic deterioration.However, the actual
effect of APRV on right heart function in ARDS patients has not been reported.
1.2 Risk/benefit assessment
1.2.1 Known potential risks
Several animal and clinical studies have confirmed that APRV can
effectively improve oxygenation and reduce the duration of mechanical

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ventilation compared with traditional mechanical ventilation mode, and the
clinical application of APRV is somewhat safe.Therefore, there is no potential
risk in this study.
1.2.2 Probability of injury
Mechanical ventilation is the most important and necessary treatment for
patients with respiratory failure, and its safety has been proven.Mechanical
ventilation
does
far
more
good
than
harm
when
compared
to
severe
life-threatening respiratory failure.
1.2.3 Degree of injury
The subjects suffered very minor injuries and had no fatal adverse events.
1.2.4 Known potential benefits
ARDS is an acute, diffuse, inflammatory lung injury that results in increased
alveolar capillary permeability, lung weight gain, and loss of aerated lung
tissue.Mechanical ventilation is the primary treatment for ARDS patients.APRV
ventilation can effectively improve oxygenation in ARDS patients and reduce the
duration of mechanical ventilation, which is very safe compared to other
mechanical ventilation modes.
1.2.5 Assessment of potential risks/benefits
Mechanical ventilation is the main treatment for ARDS patients. APRV mechanical
ventilation isa modeofmechanicalventilation thathas been usedin thetreatment ofARDS
patients for more than 20 years. Animal and clinical studies have shown that APRV
mechanical ventilation can safely and effectively improve oxygenation, reduce the duration
of mechanical ventilation and ICU stay, which can benefit ARDS patients.The potential
risks of APRV are similar to those of other mechanical ventilation modes. With
indications and contraindications, APRV has little risk and is a life-saving
treatment for patients with ARDS.
1.3 Discussion

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Acute Respiratory Distress Syndrome (ARDS) often complicated with Right
Ventricular Dysfunction (RVD), and the incidence of RVD was as high as
64%.RVD often leads to low cardiac displacement and hemodynamic failure in
patients[1].ARDS patients with RVD have a worse prognosis and a significantly
higher risk of death, which is an independent risk factor for death in ARDS
patients[2-4].
Mechanical
ventilation
is
an
important
treatment
for
ARDS
patients.Mechanical ventilation has a significant effect on hemodynamics by
influencing right ventricular function through intrathoracic positive pressure,
especially in patients with existing right ventricular insufficiency.
APRV is an inversely proportional mechanical ventilation mode with
transient
pressure
release
under
continuous positive airway
pressure
(CPAP). APRV is commonly used in the treatment of ARDS patients.APRV
improves oxygenation and is safe compared to low tidal volume lung protective
ventilation and SIMV, but randomized controlled studies have not shown that
APRV improves mortality.It is not clear whether the reason is related to APRV
increasing average airway pressure [7], thus increasing pulmonary circulation
resistance,
leading
to
right
heart
dysfunction,
or
even
hemodynamic
deterioration.However, the actual effect of APRV on right heart function in
ARDS patients has not been reported.In this study, transthoracic cardiac
ultrasound was used to evaluate right heart function, pulmonary artery pressure,
tricuspid regurgitation and hemodynamics related indicators in ARDS patients
receiving APRV mechanical ventilation, so as to fully understand the influence of
APRV mechanical ventilation mode on right heart function and hemodynamics,
which is more conducive to clinical application and avoid the occurrence of adverse
reactions.
2. Study Objective/end point
Objective: To study the effect of APRV on right ventricular function in ARDS
patients.

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Primary endpoint/outcome: Effect of APRV mechanical ventilation for 24
hours on right heart function in ARDS patients.
Secondary end point/outcome: Effects of APRV ventilation at 6h, 12h, 48h,
72h and 24h after APRV ventilation on right heart function in ARDS patients.
Effects of APRV ventilation at 6h, 12h, 24h, 48h, 72h and 24h after APRV
ventilation on hemodynamics of ARDS patients.
Mortality rate of ARDS patients on APRV mechanical ventilation at 28 days
after enrollment, length of stay in ICU, length of stay, and mortality rate in hospital.
3.Study design
3.1 Overall Design
(1). A single center prospective observational study.
(2).In ARDS patients receiving APRV mechanical ventilation, right heart function
was monitored at 6, 12, 24, 48, 72 hours after APRV mechanical ventilation, and 24
hours after APRV mechanical ventilation. Mechanical ventilation parameters,
respiratory
mechanics
and
arterial
blood
gas
analysis
were
recorded,
and
hemodynamic indexes were recorded at the same time.
3.2 Collect the following data:
（1）Demography: sex, age, height, weight
（2）Vital signs: SOFA score and APACHE II score were measured 24 hours after admission
to ICU and randomness.
（3）Physiological and biochemical indexes: blood routine, blood biochemistry (total
protein, ALB, total bilirubin, AST, ALT, GGT, blood urea nitrogen, serum creatinine),
TNI, BNP, CRP before APRV, APRV24h, 48h, 72h and at the end of APRV24h.
(4)Respiratory mechanical parameters before APRV, APRV6h, 12h, 24h, 48h, 72h
and end APRV24h.
(5)Cardiac ultrasound and hemodynamic indexes before, after, and after APRV at 6,
12, 24, 48, 72, and 24h.
(6)Fatality rate at 28 days after inclusion, length of stay in ICU, length of stay, and

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fatality rate in hospital.
3.3 Sample size
This study is to study the effect of APRV on right heart function. Referring to
previous literatures, the number of subjects is generally required to be 40, and the
number of subjects should be increased to 50 in consideration of shedding and
withdrawal, etc.
4.Study population
4.1 Diagnostic criteria
According to the Berlin 2012 ARDS diagnostic criteria
4.2 The inclusion criteria
(1). Patients who met the 2012 Berlin ARDS diagnostic criteria and underwent
invasive mechanical ventilation
(2). PEEP≥5cmH2O, oxygenation index ≤200mmHg
(3). The duration of endotracheal intubation and mechanical ventilation was less than
48h at the time of inclusion
(4). Age ≥18 and ≤80 years old
4.3 Exclusion criteria
(1). Younger than 18 years old or older than 80 years old
(2). BMI of obese patients ≥35kg/m2;
(3). Pregnant and lactating women
(4). The expected time of invasive mechanical ventilation is less than 48h
(5). Neuromuscular diseases known to require prolonged mechanical ventilation
(6). Severe chronic obstructive pulmonary disease
(7). Intracranial hypertension

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(8). Pulmonary bullae or pneumothorax, subcutaneous emphysema, mediastinum
emphysema
(9). ECMO treatment was performed when admitted to ICU
(10). Refractory shock
(11). Severe cardiac dysfunction (New York Heart Association Class ⅲor ⅳ, acute
coronary syndrome or persistent ventricular tachyarrhythmia), enlargement of the
right heart due to chronic cardiopulmonary disease, cardiogenic shock or major
cardiac surgery;
(12). Informed consent was not signed
Note: All subjects meeting either of the exclusion criteria at baseline will be
excluded from the study
5.The items and frequency of clinical and laboratory examinations to be
performed
Cardiac ultrasound examination was performed before APRV mechanical
ventilation, 6h, 12h, 24h, 48h, 72h after APRV mechanical ventilation, and 24h after
APRV mechanical ventilation. Mechanical ventilation parameters were recorded,
respiratory mechanics and arterial blood gas analysis were measured, and
hemodynamic indexes were recorded.
Collect the following data:
(1). Demography: sex, age, height, weight
(2). Vital signs: 24h SOFA score and APACHE II score after admission to ICU and
randomization
(3). Physiological and biochemical indicators: echocardiographic right heart function
monitoring, hemodynamic parameters and arterial blood gas were performed before
APRV or LTV mechanical ventilation, 6h, 12h, 24h, 48h, 72h after mechanical
ventilation, and 24h after mechanical ventilation.

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(4). Blood routine examinations, blood biochemistry (total protein, ALB, total
bilirubin, AST, ALT, GGT, blood urea nitrogen, serum creatinine), TNI, BNP and
CRP were performed at 24, 48 and 72 hours after admission to ICU and
randomization.
()Respiratory mechanical parameters before and after randomization at 24h, 48h and
72h.
Case fatality rate at 28 days after inclusion, length of stay in ICU, length of stay,
and in-hospital case fatality rate.
6.evaluation
6.1Primary and secondary end point/outcome evaluation
Primary endpoint: Effect of APRV mechanical ventilation for 24 hours on
right heart function in ARDS patients
Secondary endpoint: Effects of APRV ventilation at other time points on right
heart function in ARDS patients.
Effects of APRV ventilation at different time points on hemodynamics of ARDS
patients.
Mortality rate of ARDS patients on APRV mechanical ventilation at 28 days after
enrollment, length of stay in ICU, length of stay, and mortality rate in hospital.
6.2 Safety evaluation
APRV mechanical ventilation is a mode of mechanical ventilation for
ARDS patients, which has been proved to be safe in animal and clinical studies.
7.Adverse events and serious adverse events
Adverse event reports: Adverse medical events that occur in patients receiving
mechanical ventilation with APRV, but are not necessarily causally related to
treatment.
Reports of serious adverse events: events requiring hospitalization, prolonged
hospitalization, disability, inability to work, life threatening or death occurred during
APRV mechanical ventilation.

1
During a clinical trial, the clinical investigator is obligated to take necessary measures to
ensure the safety of the subject and to document them.Such as serious adverse events
during the process of clinical trials, researchers should immediately treatment for
participants to take appropriate measures, and report by phone or fax within 24
hours of the main researchers, the clinical test units of ethics committee, the
province, municipality directly under the central government or autonomous region
food and drug administration and the state food and drug administration
and
bidders.At the same time, a written report shall be submitted to the above institutions within
15 days.All serious adverse events must be completed in the CRF Serious adverse
Event Report Form.
All serious adverse events should be followed up until resolved, returned to
baseline, and proved unsolvable/ Permanent, change to other treatment, or death.
Medical documentation of serious adverse events should be documented in the
original documentation and follow-up tables, including results of laboratory and
ancillary tests.
The investigator and other responsible persons should analyze and
determine the causal relationship between serious adverse events in the subjects
from a clinical perspective.
8.Statistical analysis and statistical methods
Prism 4.01 was used for statistical analysis software.Because all the parameters are
non-normally
distributed,
the
data
is
represented
as
the
median
(quartile
range;Head).Friedman ANOVA of repeated measurements was used to compare the
data obtained at each step and, where appropriate, through Dunn post hoc tests using
Bonferroni correction.Qualitative data were compared with Fisher's exact test.All
comparisons were double-tailed, with P<0.05 indicating the existence of significant
differences.
9.Medical treatment and protection of subjects
9.1 Risk assessment of subjects and risk disposal measures and plans
(1) Reporting method: Any adverse events, such as subjects' subjective

1
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: record in detail, and retest according to the
situation, record its persistence, return, disappearance and other conditions.
(3) Follow-up of unalleviated adverse events. All adverse events should be
followed up until they are properly resolved or the condition is stable.
9.2 Medical treatment and protection of subjects during the study
The rights andwelfareof thesubjects will be protectedduring the study,and the
quality of their medical care willnot beaffected by their refusal to participateor
withdrawalfrom the study.
If the patient drops out of the study, we will no longer conduct study related
tests.
The investigator 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 and 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 study manner during the study, with
inclusion/exclusion criteria clearly defined, 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

1
from relatives.The subjects were also informed of possible risks to their relatives
and their rights.
Relatives of the study subjects may discuss it with other family members or
guardians before agreeing to participate.The investigator must inform relatives that
study 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 of the
study subjects will be protected and it is stressed that the quality of their medical
care will not be affected by their refusal to participate in the study.
10.2 Privacy protection
Researchobjectinformationkeptbymemberofprojectqualitycontrol,bytherelevant
forms,recordsandsamplesforstorage,withoutviolatingconfidentialityandrelatedlawsand
regulations,arbitrator, ethicscommitteeandthepharmaceuticalsupervisoryand
administrativedepartmentinspectorscancheckoriginalmedicalrecords,innotapproved
consentbeforeanyresearchinformationcannotbedisclosedtounauthorizedthirdparty.
10.3 Collection and use of specimens and data
Blood samples collected by the institute are only used for routine medical tests
during treatment, so no residual specimens will be retained.
After the study, the retained image data and other data will be used for future
research with the consent of the subjects.
10.4 Quality control and quality assurance
All physicians participating in this study were required to familiarize
themselves with the APRV mechanical ventilation pattern and the use of bedside
ultrasound.All physicians participating in this study should master respiratory
mechanics measurement methods.
The CRF form should be checked by two persons.
The project quality control leader shall conduct quality control on the study

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data every week to ensure the safety, accuracy and order of the test.
10.5 Data processing and record keeping
10.5.1 Data collection and management
The required data were collected from medical records of patients who met the
inclusion criteria and filled in paper case reports(CRF).
Data collection will be carried out by clinical researchers under the
supervision of the director, 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 shall be carried out after the training of data entry staff,
which shall be completed by two persons independently by using the double-copy entry
method.
Data review: Manual comparison of data in the case report form and thedatabase to
ensurethat the data inthe databaseare consistent withthe results in the case reportform.
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 study proposal and the statistical analysis proposal.Conduct audit to
confirm that all data have been entered into the database, all questions have been resolved,
and the analysis grouphas beendefined andjudged before locking the data.
Clinical data will be stored in a database, which shall be password protected
and logical proofreading procedures shall be set up when the database is
established.
10.5.2 Research data retention
The minimum retention time of all data and original documents should be 1
year and permission should be obtained before destruction.
10.6 Declaration of conflict of interest
There is no conflict of interest between this study and any physician

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participating in this clinical study