Assessing Ventilator Safety in Patients on Pressure-Support Ventilation
Phase: NA
Conditions: Acute Respiratory Failure, Mechanical Ventilation Complication, Ventilator-Induced Lung Injury
Sponsor: Duke University

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Duke IRB # Pro00106860 
ClinicalTrials.gov: NCT05125952 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5/26/2022 
TITLE: ASSESSING VENTILATOR 
SAFETY IN PATIENTS ON PRESSURE 
SUPPORT VENTILATION 
Short Title: ASOP 

Pro00106860: Assessing ventilator safety in patients on pressure-support ventilation 
 
Clinical Protocol Synopsis 
 
1. Title 
 
Assessing Ventilator Safety in Patients on Pressure-support Ventilation (ASOP) 
 
2. Background 
 
Ventilator-induced lung injury (VILI) is known to cause significant morbidity and 
mortality in patients with acute respiratory failure.1 Lung injury caused by large tidal volumes 
(“volutrauma”), high pressures (“barotrauma”), repetitive airway collapse (“atelectrauma”), and 
large changes in transpulmonary  pressure during a breath (“driving pressure”) are all known to 
cause VILI.2 Most studies on VILI have involved the effects of inappropriate (often excessive) 
mechanical ventilator settings. More recently, it has been noted that similar lung damage can be 
caused by large, patient generated, uncontrolled tidal volumes and driving pressures, which has 
been termed “self-induced lung injury,” or SILI3,4.These patient generated large tidal volumes 
may be disease induced (e.g. neurologic injury) or be driven by other factors (e.g. metabolic 
derangements, anxiety). Importantly, interactions of patient efforts with assisted/supported 
modes of mechanical ventilation may worsen this.   
Pressure-support ventilation (PSV) is a common mechanical ventilation mode often used 
in patients with active inspiratory efforts to help reduce patient inspiratory work and improve 
comfort. PSV effectively allows spontaneously breathing patients to determine their breath flow-
rate and breath duration, eliminating flow and cycle dyssynchrony.5 However, pressure support 
ventilation does not allow for physicians to control tidal volume or driving pressure. The risk of 
SILI may thus be increased with PSV. 
Assessing SILI risk during PSV should involve more than just measuring the delivered 
tidal volume and should also include the end inspiratory alveolar pressure (plateau pressure or 
Pplat) and the airway driving pressure (DP = Pplat-PEEP).  However, these are difficult to assess 
during PSV. Several different methods have been proposed to address these challenges7-9. 
However, to date none of these methods have been compared to assess for concordance in their 
ability to indicate an increased risk of self-induced lung injury. 
 
3. Focus of the Study and Specific Aim.  
 
ASOP is a prospective cohort study comparing three methods for assessing risk of self-
induced lung injury in patients with acute respiratory failure being managed with pressure-
support ventilation.  
 
Specific Aim: We will describe the relationship between three different assessment methods for 
risk of self-induced lung injury and compare them to a gold standard measurement. The “gold 
standard” for SILI risk will be a direct assessment of transpulmonary Pplat and DP using an 
esophageal balloon tipped catheter to measure esophageal pressure (Pes) as a surrogate for 
pleural pressure. We will compare these to three assessment techniques using only the 
conventional airway pressure monitor: a plateau pressure and DP calculation in pressure support 
ventilation, an airway occlusion test in pressure support ventilation, and a plateau pressure and 

Pro00106860: Assessing ventilator safety in patients on pressure-support ventilation 
 
DP calculation in volume-control ventilation in each patient. Our central hypothesis is that these 
three techniques will give similar results to “gold standard”.   
 
4. Study Population 
 
Inclusion Criteria: 
• 
Adult patients ( ³18) with acute respiratory failure receiving invasive mechanical 
ventilation  
• 
Managed in pressure-support mode of ventilation 
 
Exclusion Criteria:  
• 
Actively undergoing a spontaneously awakening trial or SAT 
• 
Patient or surrogate is unable to provide informed consent 
• 
Currently pregnant 
• 
Currently incarcerated 
• 
Acute exacerbation of an obstructive lung disease 
• 
Known esophageal varices or any other condition for which the attending physician 
deems an orogastric catheter to be unsafe 
• 
Esophageal, gastric or duodenal surgical procedures within the last 6 months 
 
5. Screening and Recruitment 
Study staff will identify potentially eligible patients during the study period using medical 
records and lists maintained for clinical operations. If a potentially eligible patient is identified, 
their clinical team will be contacted to ensure that the patient is appropriate for inclusion in the 
study. If deemed appropriate for participation by the clinical team, the LAR will be approached 
for consent.  
 
6. Process of obtaining informed consent 
A member of the study team will obtain permission from the legally authorized representative for 
each patient. It is necessary to obtain consent from the LAR in the study population as these 
individuals will be sedated and on mechanical ventilation. However, once the subject becomes 
capable of giving consent, the study team will approach them for study re-consent. We will obtain 
consent via paper consent.   
 
 
Paper consent process 
1. The informed consent document is provided to the patient’s LAR.  

Pro00106860: Assessing ventilator safety in patients on pressure-support ventilation 
 
2. Research staff discuss the informed consent document with the LAR in person. This step 
confirms subject/LAR identity.  
3. If the LAR decides to consent to participate, the LAR signs the informed consent document.  
4. Research staff signs consent document confirming their participation in the informed consent 
process.  
5. A copy of the consent is provided with two copies of the consent, on for the LAR and one for 
participant.  
6. Original signed consent is stored in study folder. A copy of the signed consent is uploaded to 
EHR.  
 
 
7. Data collection 
 
All data will be collected by study staff either through review of electronic health record or via 
direct measurements at the patient bedside after study enrollment.  
 
Data collected from the electronic health record at enrollment will include: 
 
• Baseline sociodemographic data 
• Admission height and weight 
• Admission diagnosis 
• Duration of mechanical ventilation prior to study enrollment 
• APACHE II Illness score 
 
Data collected at the patient bedside will included: 
 
• Baseline ventilator variables including 
o PEEP 
o Pressure support above PEEP 
o Fraction of inspired oxygen (FiO2) 
o Tidal Volume 
 
• Study specific measurements 
o Transpulmonary plateau pressure during a volume control breath 
o Transpulmonary driving pressure during a volume control breath 
o Airway plateau pressure during a volume-control breath 
o Airway driving pressure during a volume-control breath 
o Airway plateau pressure during a pressure-support breath  
o Airway driving pressure during a pressure-support breath  
o Transpulmonary plateau pressure during a pressure support breath  
o Transpulmonary driving pressure during a pressure support breath  
o Airway plateau pressure during a pressure-support breath measured using a 
Respironics NM3 device 
o Airway driving pressure during a pressure-support breath measured using a 
Respironics NM3 device 

Pro00106860: Assessing ventilator safety in patients on pressure-support ventilation 
 
o Dynamic change in airway pressure (“occlusion pressure”) and transpulmonary 
pressure during an airway occlusion maneuver during a pressure support breath 
o Respiratory effort as measured by the ventilator p(0.1).  
o Change in tidal volume with a decrease in set pressure-support 
o Change in airway and transpulmonary plateau pressure with decreased pressure support 
o Change in airway and transpulmonary driving pressure with decreased pressure support  
 
 
Data collected from the EHR after study specific measurements will include 
• Total duration of mechanical ventilation in days 
• Total duration of intensive care length of stay in days 
• Total duration of hospital length in stay in days 
• Survival to discharge 
 
No data will be collected after the patient is discharged from the hospital. 
8. Randomization 
This is a cohort study and there will be no randomization of patients to a treatment or control.  
Due to possible bias based of order of methods assessed, we will randomize the order that each 
patient is tested, including the gold standard (A) and the three methods of interest (B, C and D). 
Randomization schema will be a simple randomization of the methods for each patient, where 
each patient will be assessed on all 4 methods.  A list of method order will be created prior to 
study start with order consisting of (e.g. ABCD, BCDA, CDAB, etc).  
9. ASOP procedures.  
ASOP is a prospective cohort study comparing three methods for assessing risk of self-induced 
lung injury to a gold-standard measurement in patients with acute respiratory failure being 
managed with pressure-support ventilation.  
The study will compare the following four methods for assessing risk for SILI during PSV: 
1. The transpulmonary plateau and driving pressure during a volume control. This will be 
considered the gold standard measurement of both plateau and driving pressure.  
2. The airway plateau and driving pressure during a volume control breath. 
3. The airway plateau and driving pressure during a pressure support breath 
a. This variable will be measured in two ways. Once using an inspiratory hold on the 
Servo ventilator, and once using a Respironics NM3 device with VentAssist 
SoftWare.  
4. The dynamic change in airway pressure and transpulmonary pressure during an end 
expiratory occlusion maneuver during a pressure support breath.  
After enrollment, all baseline ventilator settings will be recorded (including PEEP, pressure 
support, tidal volume, and FiO2).  

Pro00106860: Assessing ventilator safety in patients on pressure-support ventilation 
 
The patient will then be transitioned to a study ventilator with software needed to measure 
esophageal and transpulmonary pressure. A Respironics NM3 device with VentAssist software 
will be connected to the ventilator. With this ventilator, an inspiratory hold can be performed in 
pressure support ventilation, so a plateau pressure (P plat) and driving pressure (DP) in PSV 
mode will be recorded. For all measurements with an esophageal balloon, an orogastric catheter 
fitted with esophageal balloon will be placed, with placement validated using previously 
described techniques.6 Flow cycling will be set to the minimal value.  
The following study procedure will be followed for each patient participating (note: variable 
numbers correspond to those in research data form).   
1) Record baseline demographic and clinical data in study data sheet. 
 
2)  Record baseline ventilator data in study data sheet 
a) Baseline PEEP 
b) Baseline Pressure support 
c) Baseline FiO2 
d) Baseline Respiratory rate 
e) Baseline Tidal volume 
i) Record 5 measurements in data sheet, calculate mean 
 
3) Determine study maneuver order (from predetermined randomization of maneuvers).  
 
4) Insert esophageal pressure catheter and confirm placement by Baydur maneuver. Attach 
NM3 device. Set flow cycling to the minimum amount.  
 
5) Perform following maneuvers in predetermined order, and record associated 
variables/measurements. All measurements to be done with PEEP, PS, and FiO2 the same as 
baseline reading in section 2 as above.  
 
a) Static respiratory system driving pressure (DPrs), respiraptory system driving pressure as 
measured by NM3 monitor (DPrs-NM3), and transpulmonary driving pressure (DPtp) 
and p(0.1) using inspiratory hold in pressure-support ventilation  
i) Record PEEP from ventilator(a.1)  
ii) Record PEEP from NM3 monitor (a.2) 
iii) Record end expiratory esophageal pressure (a.3) 
iv) Perform inspiratory hold  
(1) Measure airway plateau pressure (a.4) 
(2) Measure end-inspiratory esophageal pressure (a.5) 
v) Record plateau pressure as measured from NM3 monitor (a.6) 
vi) Repeat for 5 total measurements of each variable 
vii) Calculate respiratory system driving pressure from ventilator (a7 = a.4 – a.1) for each 
recorded breath 
viii) 
Calculate respiratory system driving pressure from NM3 (DPrs-NM3) monitor 
(a.8 = a.6-a.2) 

Pro00106860: Assessing ventilator safety in patients on pressure-support ventilation 
 
ix) Calculate transpulmonary driving pressure from ventilator and esophageal balloon 
([a.4-a.5]-[a.1-a.3]) for each recorded breath 
x) Record P(0.1) from ventilator for 5 breaths (a.10) 
 
b) Measure dynamic respiratory system driving pressure (DPrs-dyn) and transpulmory 
driving pressure (DPtp-dyn)  
i) Record PEEP from ventilator (b.1) 
ii) Record PEEP from NM3 monitor (b.2) 
iii) Record end-expiratory esophageal pressure during a breath (b.3) 
iv) Record maximum airway pressure (b.4) 
v) Record maximum inspiratory esophageal pressure (b.5) 
vi) Record Airway plateau pressure from NM3 monitor (b.6) 
vii) Repeat for 5 total measurements of each variable 
viii) 
Calculate dynamic driving pressure across the respiratory system (DPrs-dyn) (b.7 
= b.4-b.1) 
ix) Calculate dynamic transpulmonary driving pressure  (DPtp-dyn) (b.8 = ([b.4-b.5]-[b.1-
b.3]) 
x) Calculate the dynamic driving pressure across the respiratory system from the NM3 
monitor DPrs-Dyn-NM3 (b.6-b.2) 
 
c) Measure airway occlusion test (AOC) 
i) Measure PEEP (c.1) 
ii) Measure end expiratory esophageal pressure (c.2) 
iii) Perform expiratory hold 
(1) Expiratory hold should be held for entirety of respiratory effort until airway 
pressure returns to baseline 
(a) Measure maximum negative deflection of airway pressure (c.3) 
(b) Measure maximum negative deflection of esophageal pressure (c.4) 
iv) Repeat 5 total measurements of each variable 
v) Calculate airway occlusion pressure (AOC = c.1-c.3) for each breath 
 
d) Measure static respiratory system (DPrs-vc) and transpulmonary driving pressure (DPtp-
vc) in volume control breath 
i) Change ventilator mode to SIMV (PSV+VC), with IMV breaths set in Volume 
control.  
(1) Set PSV settings identical to baseline settings recorded in section 2.  
(2) For VC breaths, volume set to average tidal volume calculated in section 2. 
subsection D.  
(3) Set rate of IMV breaths to 1/min 
(4) Set flow rate for VC breaths to minimum 
ii) Measure PEEP (d.1) 
iii) Measure end-expiratory esophageal pressure (d.2) 
iv) Measure airway plateau (d.3) during inspiratory hold 
v) Measure end-inspiratory esophageal pressure (d.4) during inspiratory hold 
vi) Repeat for 5 total measurements of each variable  
vii) Calculate respiratory system driving pressure (DPrs-vc = d.2-d.1) 
viii) 
Calculate transpulmonary plateau pressure (d.6 = d.2-d.4) 

Pro00106860: Assessing ventilator safety in patients on pressure-support ventilation 
 
ix) Calculate driving pressure across the lung (DPtp-vc= d.6 –(d.1-d.3)) 
 
e) Measure change in airway plateau pressure and patient effort with decrease in Pressure-
support.  
i) Ventilator will be returned to baseline settings 
ii) The set pressure support will be decreased by 5 cm of H2O (to a minimum of 5 cm of 
H2O) 
iii) The new tidal volume will be recorded (e.1) 
iv) Measure PEEP (e.2) 
v) Measure end-expiratory esophageal pressure (e.3) 
vi) Perform and inspiratory hold in pressure-support 
(1) Measure airway plateau pressure (e.4) 
(2) Measure end-inspiratory esophageal pressure (e.5) 
vii) Measure a P(0.1) (e.6) 
viii) 
Repeat for 5 total measurements of each variable 
ix) Calculate new static respiratory system driving pressure (DPrs-new) (e.7=e.4-e.2) 
x) Calculate new transpulmonary driving pressure (DPl-new) (e.8=[e.4-e.5]-[e.2-e.3]) 
 
f) Return all ventilator settings to baseline.  
The order of performing these measurements will be randomized to minimize bias of the order of 
measurements.  
All study specific measurements and maneuvers will be completed in one day. After completion 
of study measurements and maneuvers, the orogastric balloon will be removed. 
A patient’s EHR will be monitored until hospital discharge to collect previously mentioned study 
specific endpoints as described above.  
Overall, we plan to enroll 25 patients.  
10. Statistical design, analyses, sample size, and power 
Statistical Design and Analysis Plan 
                        
Patient and clinical characteristics will be described overall using frequency and percent for 
categorical characteristics, and mean, standard deviation, median, and quartiles for continuous 
variables. Agreement statistics such as the intraclass correlation coefficient (ICC), Bland-Altman 
plots, and Cohen’s kappa, will be used to assess agreement of measures between the gold-
standard and the three methods of interest.  A mixed-effects regression model will be used to 
determine the difference between each method and the gold-standard taking into account the 
randomization order with results presented as the least squares mean (LSM) difference with 95% 
confidence interval (CI). All analyses will be performed using SAS 9.4 (Cary, NC) and a p-value 
<0.05 will be considered statistically significant. 
                        
Sample Size and Power 

Pro00106860: Assessing ventilator safety in patients on pressure-support ventilation 
 
                        
This is a descriptive study. The 25-person sample size reflects the pragmatics of recruitment with 
available study staff and should provide adequate power to evaluate similarities given that each 
patient acts as his/her own control.  
                                              
11. Subject Participation and Duration      
 
Study specific measurements will take one day to complete. Patients will be followed until their 
discharge from the hospital.  
 
 
12.  Study Duration  
 
We estimate that from the time enrollment opens it will require 1 year to complete all study 
activities. 
 
13. Costs to the Subject 
 
There are no costs to participants. 
 
14.  Compensation 
 
There is no compensation for participation in this study.  
 
15.  IRB 
 
Duke University Health System (DUHS) IRB will be utilized as the IRB of record for this 
project.  
 
16.  Risk-benefit assessment 
 
The overall study is believed to be a minimal risk trial. All study maneuvers and measurements, 
including esophageal balloon placement, end-inspiratory holds, and end-expiratory holds, are all 
parts of routine clinical care. Minor discomfort may be associated with esophageal tube 
placement, end-inspiratory holds, and end-expiratory holds. Minor discomfort can also be 
associated with a breath hold used for changing ventilators. Actually changing ventilators is 
minimal risk, and is again common in clinical practice (i.e. patients are often placed on travel 
ventilators to travel to have imaging studies performed). All patients, as they will be 
mechanically ventilated, should be receiving or have available analgesic and/or sedating 
medications as part of routine clinical care that should mitigate the risk of discomfort.  
 
Esophageal balloon placement and use can assist with ventilator management and may be used 
by the patients’ treatment teams after study measurements are taken, which may be an indirect 
benefit to patients who otherwise would not have a orogastric balloon placed. Placement of the 
orogastric tube with an esophageal balloon rarely could cause esophageal injury. This is more 
often associated with long-term placement of the balloon, which will not occur in this stidy.  

Pro00106860: Assessing ventilator safety in patients on pressure-support ventilation 
 
 
Additionally, as with any research, there is always a potential loss of confidentiality. Appropriate 
safeguards are in place to ensure confidentiality, as described in the RDSP. Participants’ LAR 
can choose not to participate and continue receiving normal standard of care. 
                                                       
 
 
Recruitment and informed consent procedures 
First, the Duke Institutional Review Board (IRB) will review and approve the study protocol before 
study initiation. Informed consent will be required from all participants or their legally authorized 
representative. Enrollment is completely voluntary.  
 
Protections against risk   
 
General oversight   
There are several ongoing mechanisms for monitoring the occurrence of adverse events. First, all study 
patients will be directly monitored by trained clinical staff (either a physician, respiratory therapist, or 
both) during study measurements and maneuvers to assess for adverse events. After enrollment, 
patients’ EHR will be monitored daily by study personnel, which will allow identification of any long-
term adverse events associated with orogastric balloon placement.  
 
Vulnerable populations.  We will not enroll participants from vulnerable populations (e.g., imprisoned 
persons, minors). 
 
17.  Data & safety monitoring 
 
Data Accuracy and Protocol Compliance. 
                                
The PI will supervise the study, including data management, data accuracy, and protocol 
compliance. The co-PI (Dr. Pratt) will be the chief data manager and will adhere to established 
federal and institutional safety and protection guidelines. To assure data accuracy, the co-PI will 
review data reports on a routine basis. These reports will show enrollment, missing data, and 
other values that are neither study ID- nor outcome-based.  
 
 
Adverse events (AEs), serious adverse events, (SAEs) and unanticipated problems (UPs). 
                        
It is anticipated, in this study, for AEs to be extremely rare as all interventions are part of routine 
clinical care and are associated with minimal risk. However, since enrolled patients will be 
critically ill and experiencing acute respiratory failure, it is expected that patients will have a 
number of unrelated adverse health events during the course of their hospital stay.   
 
Therefore, for this study, only adverse events related to study maneuvers and measurements and 
long-term esophageal balloon placement will be recorded.  
 
Adverse events related to study maneuvers and measurements will include: 

Pro00106860: Assessing ventilator safety in patients on pressure-support ventilation 
 
 
• A change in respiratory status requiring increasing ventilator support (e.g., a decrease in 
peripheral oxygen saturation requiring an increase in ventilator FiO2).  
• Hemodynamic instability requiring addition or up-titration of vasopressors.  
 
Adverse events related to nasogastric balloon placement will include: 
• Esophageal injury 
• Upper gastrointestinal bleeding 
                                
Like AEs, it is not anticipated that SAEs will occur. However, for this study, an SAE would be 
defined as a death related to study procedures. All serious adverse events will be reported within 
the standard timelines required to the IRB as appropriate and when applicable. 
 
As the study intervention is short, it is not expected that there will be any protocol deviations. 
Should protocol deviations or unanticipated problems occur, they will be discussed with the PI, 
documented, and reported to the IRB as appropriate and when applicable. 
 
Period and Frequency for Event Assessment and Follow-Up 
                                
Protocol deviations and other unanticipated problems, as well as AEs and SAEs, will be recorded 
throughout the study and reported, as appropriate, to the IRB when applicable. 
                                
The study team will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or until hospital discharge (for SAEs).  
 
Characteristics of an Adverse or Serious Adverse Event   
To assess relationship of an event to study intervention, the following guidelines are 
used:                         
1. Related (Possible, Probable, Definite) 
1. The event is known to occur with the study intervention.  
2.  There is a temporal relationship between the intervention and event onset. 
3. The event abates when the intervention is discontinued. 
4. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
1. There is no temporal relationship between the intervention and event onset.  
2. An alternate etiology has been established.                                
Expectedness 
 
The Study PI will be responsible for determining whether an event is expected or unexpected. An 
event will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the intervention. 
 
Severity 

Pro00106860: Assessing ventilator safety in patients on pressure-support ventilation 
 
 
The following scale will be used to grade adverse events: 
1. Mild: no intervention required; no impact on activities of daily living (ADL) 
2. Moderate: minimal, local, or non-invasive intervention indicated; moderate impact on 
ADL 
3. Severe: significant symptoms requiring invasive intervention; subject seeks medical 
attention, needs major assistance with ADL                                                   
                                
Reporting Procedures 
                                                                   
Serious (fatal or life-threatening) SAEs that are unanticipated and that are related to the 
intervention will be reported to the IRB within 5 days of study staff’s knowledge of the SAE. 
                                                
Protocol Deviations and Other Unanticipated Problem Reporting 
                                
Incidents or events that meet the reporting criteria, as outlined by the Duke IRB, will be reported 
to the Duke IRB as needed. 
 
The following will be included, at a minimum: 
• 
A detailed description of the event, incident, experience, or outcome. 
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the unanticipated problem.                                
Compliance regarding Adverse Event Reporting. 
                                
The study team will be required to document and report adverse events (including serious 
adverse events) to the Institutional Review Board (IRB), as appropriate and in line with 
institutional reporting criteria. 
                                
 
17. Privacy, Data Storage & Confidentiality 
 
Privacy 
                                
The study team will closely safeguard participant privacy regarding protected health and 
personal information. A study ID number will be generated at the time of consent and will be 
maintained in a secure file (e.g., linker file) which will contain the participant. Further, names, 
birth dates, telephone numbers, and addresses will be stored securely as described in the RDSP 
and only accessible by delegated study team members.  
 
 
Data Storage 

Pro00106860: Assessing ventilator safety in patients on pressure-support ventilation 
 
We will use a secure REDCap database to collect and store all study-related information.  
Additionally, datasets will be stored on the secured Duke server \\duhs-vclin-
nc1\dusom_biostats_fs\data\BiostatsCore\CRU\Pulmonology\\ for statistical analysis. 
                                
Confidentiality 
                                    
Subjects will not be identified on any study reports. University firewalls, multiple passwords, 
and encryption programs protect the security of the electronic data, which will be housed on a 
highly secure Duke University server. All personal computers are located in lockable offices and 
are accessible only by frequently changed passwords. The server room is accessible only to 
designated University Systems Administrators. 
 
      
References: 
 
1. 
Beitler JR, Malhotra A, Thompson BT. Ventilator-induced Lung Injury. Clin Chest Med. 
2016;37(4):633-646. 
2. 
Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. 2013;369(22):2126-
2136. 
3. 
Sottile PD, Albers D, Smith BJ, Moss MM. Ventilator dyssynchrony - Detection, 
pathophysiology, and clinical relevance: A Narrative review. Ann Thorac Med. 2020;15(4):190-
198. 
4. 
Grieco DL, Menga LS, Eleuteri D, Antonelli M. Patient self-inflicted lung injury: implications for 
acute hypoxemic respiratory failure and ARDS patients on non-invasive support. Minerva 
Anestesiol. 2019;85(9):1014-1023. 
5. 
Hess DR. Ventilator waveforms and the physiology of pressure support ventilation. Respir Care. 
2005;50(2):166-186; discussion 183-166. 
6. 
Mauri T, Yoshida T, Bellani G, et al. Esophageal and transpulmonary pressure in the clinical 
setting: meaning, usefulness and perspectives. Intensive Care Med. 2016;42(9):1360-1373.