Effect of Esophageal Pressure Measurement to Determine Optimal Positive End-expiratory Pressure Compared to Usual Care in Obese Patients Receiving Mechanical Ventilation
Phase: NA
Conditions: Obesity, Morbid, Ventilator-Induced Lung Injury, Respiratory Failure
Sponsor: University of North Carolina, Chapel Hill

 
 
Providing Optimal PEEP During Mechanical Ventilation for Obese 
Patients using Esophageal Balloon 
 
 
NCT number NCT03951064 
Document Date 02/26/2021 
 

1 
Master Protocol: Optimal PEEP for Prevention of VILI 
Providing Optimal PEEP During Mechanical Ventilation for Obese Patients using 
Esophageal Balloon: Master Protocol 
 
Complete Title:  
 
Effect of Esophageal Pressure Measurement to Determine Optimal Positive 
End-expiratory Pressure Compared to Usual Care in Obese Patients 
Receiving Mechanical Ventilation  
Short Title: 
PROP OPEN - Providing Optimal PEEP During Mechanical Ventilation for 
Obese Patients using Esophageal Balloon 
Protocol Date: 
 
April 30, 2019 
Amendment 1 Date: 
February 26, 2021 
Amendment 2 Date:  
Amendment 3 Date: 
Amendment 4 Date:  
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
Shannon Carson, MD 
CB# 7020, 130 Mason Farm Rd 
4th Floor Bioinformatics Bldg 
Chapel Hill, NC 27599 
Phone: 919-966-2531 
Email: shannon_carson@med.unc.edu 
 
Co-Investigators:  
Thomas Bice, MD, MSc 
Ogugua Obi, MD, MPH  
Charles Bangley, RRT 
Thomas Devlin, RRT 
Agathe Ceppe, MS 
 
 
 

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Master Protocol: Optimal PEEP for Prevention of VILI 
Table of Contents 
1 
BACKGROUND AND RATIONALE ........................................................................................................................... 7 
1.1 
INTRODUCTION.......................................................................................................................................................................... 7 
1.2 
DESCRIPTION OF INTERVENTION ............................................................................................................................................... 7 
1.3 
RELEVANT LITERATURE AND DATA .......................................................................................................................................... 7 
2 
STUDY OBJECTIVE.................................................................................................................................................. 7 
2.1 
PRIMARY OBJECTIVE ................................................................................................................................................................. 8 
3 
INVESTIGATIONAL PLAN ....................................................................................................................................... 8 
3.1 
STUDY DESIGN .......................................................................................................................................................................... 8 
3.2 
ALLOCATION TO TREATMENT GROUPS ..................................................................................................................................... 8 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF PARTICIPANTS .......................................................................................... 8 
3.4 
STUDY POPULATION .................................................................................................................................................................. 8 
4 
STUDY PROCEDURES ............................................................................................................................................. 9 
4.1 
SCREENING/ENROLLMENT ........................................................................................................................................................ 9 
4.2 
RANDOMIZATION, CONCEALMENT, AND BLINDING ................................................................................................................... 9 
4.3 
INTERVENTION PROCEDURES ..................................................................................................................................................... 9 
4.4 
PARTICIPANT COMPLETION/ WITHDRAWAL .............................................................................................................................. 9 
5 
STUDY EVALUATIONS AND MEASUREMENTS ..................................................................................................... 9 
5.1 
MEASUREMENTS ....................................................................................................................................................................... 9 
5.2 
OTHER MEASUREMENTS .......................................................................................................................................................... 12 
6 
STATISTICAL CONSIDERATION ............................................................................................................................ 13 
6.1 
PRIMARY ENDPOINT ................................................................................................................................................................ 13 
6.2 
STATISTICAL METHODS .......................................................................................................................................................... 13 
6.3 
SAMPLE SIZE AND POWER ....................................................................................................................................................... 13 
7 
SAFETY MANAGEMENT ....................................................................................................................................... 14 
7.1 
RISKS TO HUMAN SUBJECTS ................................................................................................................................................... 14 
7.2 
DATA AND SAFETY MONITORING PLAN .................................................................................................................................. 14 
7.3 
DATA AND SAFETY MONITORING BOARD (DSMB) ................................................................................................................ 15 
8 
DATA COLLECTION AND MANAGMENT ............................................................................................................. 15 
9 
RECRUITMENT STRATEGY ................................................................................................................................... 16 
10 CONSENT PROCESS ............................................................................................................................................. 16 
11 PLANS FOR PUBLICATION ................................................................................................................................... 17 
12 REFERENCES ........................................................................................................................................................ 17 
12.1 
ARDSNET PEEP/FIO2 TABLE ................................................................................................................................................ 18 
 

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Master Protocol: Optimal PEEP for Prevention of VILI 
Abbreviations and Definitions of Terms 
 
 
 
Abbreviation 
Definition 
PEEP 
Positive end expiratory pressure 
MV 
Mechanical ventilation 
ARDS 
Acute respiratory distress syndrome 
Ptp 
Transpulmonary pressure 
Pes 
Esophageal Pressure 
Paw 
Airway pressure 
FiO2 
Fraction of inspired oxygen 
SpO2 
Peripheral oxygen saturation 
MICU 
Medical intensive care unit 
RASS 
Richmond Agitation-Sedation Scale 
CAM-ICU 
Confusion Assessment Method for the ICU 
SOFA 
Sequential Organ Failure Assessment 
APACHE 
Acute Physiology and Chronic Health Evaluation 
VFD 
Ventilator-free days 
LAR 
Legally authorized representative 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

4 
Master Protocol: Optimal PEEP for Prevention of VILI 
Protocol Synopsis 
Study Title 
Effect of Esophageal Pressure Measurement to Determine 
Optimal Positive End-expiratory Pressure Compared to Usual 
Care in Obese Patients Receiving Mechanical Ventilation 
 
Funder 
Departmental funds 
Study Rationale 
The use of positive end-expiratory pressure (PEEP) in 
mechanical ventilation is important to reduce the collapse of 
alveoli between breaths. This atelectasis increases the 
patient’s work of breathing and impairs oxygenation. In 
addition, atelectrauma can lead to ventilator-induced lung 
injury through repetitive shear injury. There is a patient-specific 
response to PEEP titration, but PEEP titration is frequently not 
guided by individual patient data. Obese patients have less 
compliant chest walls, which increases the apparent airway 
pressure required to provide mechanical ventilation. Titration 
of PEEP to levels high enough to prevent atelectasis and 
improve chest wall compliance in these patients yields 
apparently unsafe pressures. Yet these pressures are not likely 
transmitted to the alveoli. In order to evaluate the pressure 
transmitted to the alveoli, one should consider the pleural 
pressure. Direct measurement of the pleural pressure is highly 
invasive and poses risk to the patient. However, estimation of 
the pleural pressure using an esophageal pressure monitor is 
significantly less invasive and provides an acceptable 
alternative for estimation of transpulmonary pressure (Ptp). 
Preliminary work by members of the research group evaluated 
time to wean from mechanical ventilation in obese patients 
requiring tracheostomy. Use of Ptp to guide PEEP choice 
resulted in a significant reduction in the median time to wean, 
from 14 days to 3.5 days (p=0.012).  We propose that 
esophageal pressure measurement can guide optimal PEEP 
selection in obese patients who require mechanical ventilation 
and reduce their time on the ventilator. 
Study Objective(s) 
To evaluate whether esophageal pressure measurement to 
determine optimal PEEP in obese patients receiving 
mechanical ventilation can reduce time on the ventilator when 
compared to usual care. 
Study Design 
 
Randomized-controlled clinical trial. Patients will be enrolled 
within 4 days of mechanical ventilation and randomized 1:1 to 
titration of PEEP based on esophageal balloon pressures or 
based on the “High PEEP” ARDSnet PEEP/FiO2 table. All 
patients will have esophageal balloons placed with baseline 
measurement of Ptp. Patients randomized to the intervention 
arm will then undergo titration of PEEP based on Ptp 
measurements to achieve “Optimal PEEP,” defined as end 
expiratory Ptp of 0 to +2 cm H2O. 

5 
Master Protocol: Optimal PEEP for Prevention of VILI 
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria: Obese adults (BMI ≥ 40) admitted to the 
medical ICU at UNC Hospitals or Vidant Medical Center at ECU 
with acute respiratory failure requiring mechanical ventilation. 
 
Exclusion Criteria: 
1. Refusal to give consent by subject or LAR 
2. Abdominal compartment syndrome 
3. Chest tube for pneumothorax 
4. Having been on a ventilator for >4 days 
5. Suspicion of or known intracranial hypertension 
6. Anticipated extubation within 24 hours 
7. Chronic ventilator dependence 
8. Condition that precludes placement of an esophageal 
balloon (esophageal or nasopharyngeal pathology 
preventing insertion of the esophageal balloon catheter, 
severe thrombocytopenia, or coagulopathy) 
9. Incarceration 
10. Not expected to survive >48 hours 
11. Unable to obtain consent from subject or LAR 
12. Unable to obtain consent due to a language barrier 
Number Of Subjects  
 
76 patients  
Study Duration 
Each subject’s participation will last for up to 28 days. The 
entire study is expected to last about 12-24 months. 
Study Phases 
  
(1) Screening: Screening for eligibility and obtaining consent 
for enrollment. 
(2) Pre-Intervention: Esophageal balloon placed and baseline 
data collected. 
(3) Intervention: PEEP titrated to achieve Optimal PEEP in the 
intervention group. Ptp Measurements will be obtained daily 
and adjustments to PEEP will occur daily. 
(4) Subject Completion/Withdrawal: Study will conclude for 
each patient at 28 days after enrollment or hospital discharge. 
Efficacy Evaluations 
Primary evaluation measurements that will be used to assess 
the efficacy of the intervention are ventilator free days at day 
28. Differences between control and intervention groups will be 
attributed to differences in PEEP management. 
Safety Evaluations 
Periodic review will be performed by the NC TraCS DSMB. 
They will review aggregate safety data after 25, 50, and 75% 
enrollment to ensure there are not safety differences between 
the groups in hypotension requiring vasopressors and 
development of pneumothorax. All patients will have 

6 
Master Protocol: Optimal PEEP for Prevention of VILI 
continuous monitoring of HR, BP, and oxygenation per ICU 
protocol to monitor patient safety. 
 
Statistical And 
Analytic Plan 
This is a randomized, controlled trial to evaluate the effect of 
using Optimal PEEP based on an esophageal balloon 
measurement on duration of mechanical ventilation. We 
hypothesize that using Ptp to identify optimal PEEP will reduce 
time on the ventilator and therefore increase the ventilator free 
days at day 28. The primary outcome is the number of 
ventilator-free days, defined as the number of days alive and 
ventilator-free by day 28. Differences between the two groups 
in the primary outcome will be analyzed using independent t-
tests and a linear regression model adjusting for BMI, 
abdominal girth, and Ptp. 
DATA AND SAFETY 
MONITORING PLAN 
The PI will be responsible for maintaining patient data and 
ensuring accuracy of the data collected. All patient data will be 
collected using REDCap through the NC TraCS system. 
REDCap allows for immediate data validation and range 
setting to reduce the likelihood of erroneous data entry. Data 
created for analysis will be de-identified and secured on a 
password protected UNC School of Medicine network hard 
drive. All investigators will be trained on completing the 
electronic case report form. 
 
Patient safety will be monitored with continuous cardiovascular 
monitoring by the critical care team. Subject stopping rules will 
be in place to end the study intervention, including refractory 
hypotension, development of pneumothorax, or changes in 
oxygenation or hemodynamics that the primary team feels may 
be related to changes in PEEP. 
 
 
 
 
 

7 
Master Protocol: Optimal PEEP for Prevention of VILI 
1 
BACKGROUND AND RATIONALE 
1.1 
Introduction 
This is a randomized, controlled trial evaluating the effect of “optimal PEEP” compared to 
standardized PEEP titration on duration of mechanical ventilation in obese adult patients with 
acute respiratory failure requiring mechanical ventilation. 
1.2 
Description of Intervention 
All patients in both groups will have an esophageal balloon catheter inserted by a research 
investigator. The catheter will be inserted into their nare while upright (head of bed >30 degrees) 
to a depth slightly more than the estimated distance from the lower sternum to the back of the 
ear (typically around 60 cm). Gastric positioning will be confirmed with abdominal compression 
testing and the catheter then retracted 10 – 20cm into the lower esophagus. Placement will be 
confirmed with the presence of cardiac oscillations on the esophageal probe. The probe will then 
be secured to the patient’s nasal opening using tape. Pressures (Pes, Paw, and Ptp) are 
measured directly through the ventilator. Values of Paw, Pes, and Ptp will be collected daily in 
both groups. The waveforms of Paw, Pes, and Ptp will be visualized on the ventilator. Ptp is 
obtained from Paw – Pes. PEEP will be increased on the ventilator to achieve a Ptp between 0 
and +2 cm H2O (“Optimal PEEP”). Measurements will be obtained daily and adjustments to 
PEEP will occur daily. PEEP will be reduced below Optimal PEEP in the setting of hemodynamic 
compromise (requiring increasing vasoactive medications for blood pressure support). 
1.3 
Relevant Literature and Data 
The use of PEEP in mechanical ventilation is important to reduce the collapse of alveoli between 
breaths. This atelectasis increases the patient’s work of breathing and impairs oxygenation. In 
addition, atelectrauma can lead to ventilator-induced lung injury (VILI) through repetitive shear 
injury. (1) There is a patient-specific response to PEEP titration, but PEEP titration is frequently 
not guided by individual patient data. Obese patients have less compliant chest walls, which 
increases the apparent airway pressure required to provide mechanical ventilation. Titration of 
PEEP to levels high enough to prevent atelectasis and improve chest wall compliance in these 
patients yields apparently unsafe pressures. Yet these pressures are not likely transmitted to the 
alveoli. (2) In order to evaluate the pressure transmitted to the alveoli, one should consider the 
pleural pressure. Direct measurement of the pleural pressure is highly invasive and poses risk 
to the patient. However, estimation of the pleural pressure using an esophageal pressure 
monitor is significantly less invasive and provides an acceptable alternative for estimation of 
transpulmonary pressure (Ptp). (3–6) Preliminary work by members of the research group 
evaluated time to wean from mechanical ventilation in obese patients requiring tracheostomy. 
Use of Ptp to guide PEEP choice resulted in a significant reduction in the median time to wean, 
from 14 days to 3.5 days (p=0.012). (7) We propose that esophageal pressure measurement 
can guide optimal PEEP selection in obese patients who require mechanical ventilation and 
reduce their time on the ventilator. 
2 
STUDY OBJECTIVE  
The overall purpose of the study is to evaluate the effect of using an esophageal balloon 
determined optimal PEEP management strategy on the duration of mechanical ventilation in 
obese adult patients with acute respiratory failure requiring mechanical ventilation.  

8 
Master Protocol: Optimal PEEP for Prevention of VILI 
2.1 
Primary Objective 
To determine if titration of PEEP to Optimal PEEP results in a reduction of the duration of 
mechanical ventilation in obese adults in a medical ICU.  
3 
INVESTIGATIONAL PLAN  
3.1 
Study Design 
We will conduct an open label randomized controlled clinical trial to evaluate the impact of 
titration to Optimal PEEP compared to use of a standardized PEEP table on the duration of 
mechanical ventilation in obese patients with acute respiratory failure. Patients will be followed 
for 28 days to evaluate for ventilator-free days. Blinding of the clinical team will not be possible 
due to the differences in treatment approach, including the performance of spontaneous 
breathing trials. 
3.2 
Allocation to Treatment Groups 
Patients will be randomized 1:1 in blocks of 2, 4, or 6  to Optimal PEEP vs High-PEEP ARDSnet 
PEEP/FiO2 table PEEP management. Randomization will be completed using the REDCap 
randomization module. 
3.3 
Study Duration, Enrollment and Number of Participants 
Enrollment will continue until 38 participants have been enrolled in each group (76 participants 
total). The medical ICU (MICU) admits approximately 150 per month, 40-50% of whom require 
mechanical ventilation. Based on a previous evaluation of lung protective ventilation in our 
hospital, approximately 45% of our patients requiring mechanical ventilation have a BMI ≥40. 
Therefore, the MICU conservatively admits approximately 24 patients a month that meet 
inclusion criteria. Based on expected enrollment of at least 3-4 participants per month, the trial 
is expected to complete enrollment within 24 months. Each patient’s participation will last 28 
days or until death or hospital discharge. 
3.4 
Study Population 
Inclusion Criteria: Obese adults (BMI ≥ 40) admitted to the MICU at UNC Hospital or the ICU at 
Vidant Medical Center ECU with acute respiratory failure requiring mechanical ventilation. 
Exclusion Criteria: 
1. Refusal to give consent by the subject or their LAR 
2. Abdominal compartment syndrome 
3. Chest tube for pneumothorax 
4. Having been on a ventilator for >4 days 
5. Suspicion of or known intracranial hypertension 
6. Anticipated extubation within 24 hours 
7. Chronic ventilator dependence 
8. Condition that precludes placement of an esophageal balloon (esophageal or 
nasopharyngeal pathology preventing insertion of the esophageal balloon catheter, 
severe thrombocytopenia or coagulopathy) 
9. Incarceration 
10. Not expected to survive >48 hours 
11. Unable to obtain consent from subject or LAR 
12. Unable to obtain consent due to a language barrier 

9 
Master Protocol: Optimal PEEP for Prevention of VILI 
4 
STUDY PROCEDURES 
4.1 
Screening/Enrollment 
Daily screening of all intubated patients in the MICU at UNC Hospital and the ICU at Vidant 
Medical Center ECU will be conducted by the research team. Intubated patients will be evaluated 
for inclusion and exclusion criteria. For patients meeting inclusion criteria, the primary clinical 
team will then be approached for permission to enroll prior to approaching families of patients 
for enrollment. 
4.2 
Randomization, Concealment, and Blinding 
Patients will be randomized 1:1 in random blocks of 2, 4, or 6 to optimal PEEP vs standard PEEP 
management. Allocation concealment will be performed through the REDCap randomization 
module. Due to the obvious treatment differences between the two groups, blinding of treatment 
group will be impossible. However, we will have one outcome assessor who will have access 
only to the data necessary to determine the primary outcome (VFD at 28-days), and this 
assessor will be blinded to treatment group using built-in REDCap tools. 
4.3 
Intervention procedures 
All patients in both groups will have an esophageal balloon catheter inserted by a research 
investigator. The catheter will be inserted into their nare while upright (head of bed >30 degrees) 
to a depth slightly more than the estimated distance from the lower sternum to the back of the 
ear (typically around 60 cm). Gastric positioning will be confirmed with abdominal compression 
testing and the catheter then retracted 10 – 20cm into the lower esophagus. Placement will be 
confirmed with the presence of cardiac oscillations on the esophageal probe. The probe will then 
be secured to the patient’s nasal opening using tape.  
Pressures (Pes, Paw, and Ptp) are measured directly through the ventilator. Values of Paw, Pes, 
and Ptp will be collected daily in both groups. 
4.4 
Participant Completion/ Withdrawal 
Participants will complete the study at the time of death or the conclusion of 28 days, whichever 
occurs first.  
Early completion of the trial for each participant will occur if any of the following outcomes are 
met: 
a. Patient or family withdraw consent for the study 
b. The clinical team feels that the patient no longer meets appropriateness for the study 
c. Patient develops and adverse effect felt possibly related to the intervention (refractory 
hypotension, nasopharyngeal bleeding, pneumothorax, etc) 
 
5 
STUDY EVALUATIONS AND MEASUREMENTS  
5.1 
Measurements 
Procedures for PEEP and FiO2 Titration 
Both groups will have their FiO2 titrated based on results of the PaO2 from an arterial blood gas, 
if available, or SpO2 values if no arterial blood gas is obtained. PEEP titration will vary by group 
as below. 

10 
Master Protocol: Optimal PEEP for Prevention of VILI 
Setting PEEP in Intervention Group 
The waveforms of Paw, Pes, and Ptp will be visualized on the ventilator. Ptp is obtained from 
Paw – Pes. PEEP will be increased on the ventilator to achieve a Ptp between 0 and +2 cm H2O 
(Optimal PEEP). Measurements will be obtained daily and adjustments to PEEP will occur daily. 
PEEP will be reduced below Optimal PEEP in the setting of hemodynamic compromise 
(requiring increasing vasoactive medications for blood pressure support). 
Setting PEEP in Control Group 
PEEP in the control group will be determined by High PEEP ARDSnet PEEP/FiO2 table. Titration 
of PEEP will occur when clinically indicated by PaO2 or SpO2, and FiO2. We chose the High 
PEEP table based on the clinical suspicion that obese patients may require higher PEEP levels 
on average than non-obese patients to balance the additional pressure of their chest wall. In 
addition, EPVent2, a study of esophageal balloon PEEP titration in patients with ARDS utilized 
the High PEEP table. Patients with moderate and severe ARDS benefit from higher levels of 
PEEP. (8) 
Procedures for Assessment of Readiness for Extubation 
Both groups will have a daily assessment of readiness for extubation performed by the 
Respiratory Therapist and bedside RN according to the standard clinical protocol. Criteria for 
both groups to undergo a spontaneous breathing trial (SBT) will be the following: 
1) 
Not in prone position 
2) 
No increased ICP 
3) 
No active seizures 
4) 
No alcohol withdrawal requiring escalating treatment 
5) 
No active myocardial ischemia in discussion with nursing or physician 
6) 
No unstable spine fractures 
7) 
No free muscle flaps 
8) 
FiO2 ≤ 50% and SpO2 ≥ 90% 
9) 
Minute Ventilation < 15 L/min 
10) 
Minimal vasopressors (norepinephrine < 5mcg/min or 0.05 mcg/kg/min, 
dopamine/dobutamine ≤ 5 mcg/kg/min) 
11) 
HR < 140 
12) 
RR ≤ 35 
13) 
SBP > 90 and < 180 
Failure of an SBT will be demonstrated if any of the following criteria are met: 
1) 
SpO2 < 90% sustained ≥ 5 minutes 
2) 
Spontaneous VT ≤ 4ml/kg IBW – sustained ≥ 5 minutes 
3) 
Respiratory Rate ≥ 35/min  
4) 
Rapid Shallow Breathing Index >105 
5) 
Other signs of respiratory distress (distress = 2 or more) 
6) 
HR > 140 
7) 
Marked accessory muscle use 
8) 
Abdominal paradox (belly breathing) 
9) 
Diaphoresis 

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Master Protocol: Optimal PEEP for Prevention of VILI 
Failure of an SBT will be determined by the bedside RT based on current policy (PolicyStat ID: 
4745433). If a patient fails an SBT, they will be returned to their previous ventilator settings until 
the next daily assessment. If the patient tolerates a 30-minute SBT, they will be returned to their 
previous ventilator settings for 60 minutes, then extubated to an appropriate oxygen delivery 
device. Ventilator settings during the SBT and extubation procedures will vary between groups 
as below. Blinding of the respiratory therapist determining eligibility for SBT to treatment arm will 
not be possible because of the differences between SBT protocols. However, the study team 
will make no determinations of readiness for extubation. If a member of the study team is on 
service during the time of potential enrollment, these patients will be excluded to avoid bias. 
SBT and Extubation Procedure for Intervention Group 
Patients in the Intervention group will undergo an SBT regardless of their PEEP level. The PEEP 
that generates a Ptp of 0 will be considered their optimal PEEP, and this will not be lowered for 
the SBT. The Intervention Group SBT will consist of a trial of a pressure support of 5 cm H2O 
and Optimal PEEP.  
SBT and Extubation Procedure for Control Group 
Patients in the Control group will undergo an SBT when they reach a PEEP ≤8 cm H2O. This 
is the current standard of care based on the SBT protocol at UNC Hospitals. SBT and extubation 
prior to meeting these criteria will be based on primary medical team’s discretion and will be 
recorded for analysis and safety tracking. 
Procedures for ventilator weaning after tracheostomy 
Any patient who fails to be eligible for extubation or fails extubation will be eligible for 
tracheostomy per usual unit protocol. The study team will play no part in the decision to proceed 
with tracheostomy for ventilator weaning. After tracheostomy, it is routine practice to forego SBT 
and proceed with trials of liberation from the ventilator with oxygen delivered by an aerosol 
tracheostomy collar (“trach collar trials” or TCT). The same criteria are used to perform a TCT 
as an SBT above. The two groups will have different approaches to TCT. 
TCT Procedure common to both groups 
TCT will proceed for up to 12 hours as tolerated by the patient. Interval mechanical ventilation 
will be provided using a control mode of mechanical ventilation (typically PRVC with 6-8 ml/kg 
of IBW tidal volume). After 2 successful 12-hour TCT, a subsequent 24-hour TCT will be 
performed with no plan for interval mechanical ventilation. If the patient tolerates >48 hours of 
time free from mechanical ventilation, they will be considered liberated from mechanical 
ventilation. If they fail the 24-hour TCT, they will be placed back on mechanical ventilation and 
a subsequent 24-hour trial will be performed the following day. This pattern will continue until the 
patient is successfully liberated from mechanical ventilation. 
TCT Procedure for Intervention Group 
Based on the use of optimal PEEP in this group, and the experience in the previous study 
protocol (7), we will place patients in the Intervention group on TCT ONLY with a speaking valve. 
This simulates the normal process of utilizing the upper airway to maintain lung inflation that is 
performed automatically when a patient does not have an artificial airway.  

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Master Protocol: Optimal PEEP for Prevention of VILI 
TCT Procedure for Control Group 
The control group will be placed on TCT with no requirement for speaking valve. They may utilize 
a speaking valve if tolerated and desired, but there is no requirement as there is in the 
Intervention group. 
5.2 
Other measurements 
Variable 
Source 
How Measured 
Baseline 
Daily 
Completion 
Outcomes 
Ventilator free days at day 
28 (Primary outcome) 
EMR 
Days alive and free of the 
ventilator 
 
 
X 
Reintubation 
EMR 
Intubated within 72 hours of 
extubation 
 
X 
X 
ICU Length of Stay 
EMR 
Days 
 
 
X 
Hospital Length of Stay 
EMR 
Days 
 
 
X 
Tracheostomy 
EMR 
Y/N 
 
 
X 
Extubation prior to meeting 
established criteria 
EMR 
Y/N 
 
 
X 
Highest RASS 
EMR 
-5 to +4 (single highest value 
used) 
X 
X 
 
Lowest RASS 
EMR 
-5 to +4 (single lowest value 
used) 
X 
X 
 
Exposures 
Esophageal pressure (Pes) 
Ventilator 
cm H2O 
X 
X 
 
Airway pressure (Paw) 
Ventilator 
cm H2O 
X 
X 
 
Transpulmonary pressure 
(Ptp) (inspiratory and 
expiratory) 
Ventilator 
cm H2O 
X 
X 
 
PEEP 
Ventilator 
cm H2O 
X 
X 
 
Opioids 
EMR 
Continuous, bolus sch, bolus 
prn, oral sch, oral prn 
X 
X 
 
Propofol 
EMR 
Y/N 
X 
X 
 
Dexmedetomidine 
EMR 
Y/N 
X 
X 
 
Benzodiazepines 
EMR 
Continuous, bolus sch, bolus 
prn, oral sch, oral prn 
X 
X 
 
Antipsychotics 
EMR 
Sched, PRN 
X 
X 
 
Neuromuscular blockade 
EMR 
Y/N 
X 
X 
 
Corticosteroid use 
EMR 
Y/N 
X 
X 
 
Fluid Balance 
EMR 
Net fluid balance prior to 
extubation 
 
X 
 
Safety Measures 
 
 
 
 
 
Vasopressor requirement 
EMR 
norepinephrine equivalents(9) 
X 
X 
 
Pneumothorax 
EMR 
Y/N 
X 
X 
 
Other Variables of Interest 
Age 
EMR 
Years 
X 
 
 
Race/Ethnicity 
 
 
 
 
 
BMI 
EMR 
kg/m2 
X 
 
 
Partial Pressure of Oxygen 
(PaO2) 
EMR 
mmHg 
X 
X 
 
Oxygen Saturation (SpO2) 
EMR 
% 
X 
X 
 

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Master Protocol: Optimal PEEP for Prevention of VILI 
PaO2/FiO2 ratio 
Calculated 
Number 
X 
X 
 
SpO2/FiO2 ratio 
Calculated 
Number 
X 
X 
 
Charlson Comorbidities 
EMR 
Y/N 
X 
 
 
Waist circumference 
EMR 
cm 
X 
 
 
 
 
 
 
 
 
CAM-ICU 
EMR 
Positive/Negative 
X 
X 
 
SOFA 
EMR 
Calculated 
X 
 
 
COVID (y/n) 
EMR 
Y/N 
X 
 
 
 
6 
STATISTICAL CONSIDERATION    
6.1 
Primary Endpoint 
The primary outcome is the number of ventilator-free days (VFD), defined as the number of days 
alive and ventilator-free by day 28. The assessment of the primary outcome will be conducted 
by a study team member after subject completion in the study. In order to minimize potential 
bias, this team member will be blinded to treatment arm assignment. 
6.2 
Statistical Methods 
All continuous variables (see 5.2) will be described using mean and standard deviation, with 
associated 95% confidence intervals, or median with interquartile range as appropriate based 
on normality of distribution. All categorical variables will be described with frequency and 
percentage. 
To determine if the optimal PEEP has an effect on the duration of mechanical ventilation 
compared to usual PEEP, the primary outcome will be analyzed with a 2-sided independent t-
test.  As secondary analysis, the associations between the primary outcome and exposures and 
demographic variables will be further analyzed using linear regression models.   
The impact of optimal PEEP vs standardized PEEP titration will be assessed on all other 
variables with independent t-tests or chi-square tests as appropriate. All secondary outcomes, 
as described in 5.2, will be further analyzed with either linear regression models or logistic 
models, using demographic and exposure variables as predictors. 
All tests will be 2-sided, and p-values < 0.05 will be considered significant. Tests with p-values 
above 0.05 will be considered inconclusive. Missing values will be ignored.  
No interim analyses for efficacy or futility are planned, but interim analyses will be conducted for 
safety. 
6.3 
Sample Size and Power 
We utilized preliminary data from earlier studies of mechanical ventilation in the obese to 
establish a baseline. With a mean duration of mechanical ventilation of 7 days with a standard 
deviation of 2.9 days, we expect the control group to have 21 ventilator free days. We estimate 
that we could reasonably see an effect in the intervention group that reduces the duration of 
mechanical ventilation by 3 days. With a power of 80% and alpha=0.05, we would need 16 
patients per group, for a total of 32 patients. Would the effect be only a reduction of mechanical 
ventilation by 2 days, we would need 34 patients in each group for a total of 68 patients. Because 
the population in our study would be expected to have a lower mean duration of mechanical 

14 
Master Protocol: Optimal PEEP for Prevention of VILI 
ventilation, we anticipate we may find a smaller effect size. Including a possible 10% dropout, 
we will target a sample size of 76 (38 per group) to safely achieve our goals. 
7 
SAFETY MANAGEMENT 
7.1 
Risks to Human Subjects 
The placement of the esophageal balloon catheter in carefully selected patients (see exclusion 
criteria above) confers a relatively small risk to the patient (such as trauma to the nasopharynx, 
esophageal irritation, stimulation of cough or vomiting). Adverse events possibly related to 
mechanical ventilation and PEEP titration will be defined as new development of pneumothorax 
and hypotension thought to be related to changes in mechanical ventilation. Despite these 
theoretical concerns, no adverse effects were seen in a small randomized trial using an 
esophageal balloon to titrate to optimal PEEP in patients with ARDS. (5) 
7.2 
Data and Safety Monitoring Plan 
All participants will be continuously monitored by critical care nurses under the guidance of 
critical care physicians per individual ICU protocols.  
Stopping rules and procedures 
Subject stopping rules will be the development of any of the following after randomization: 
• New pneumothorax 
o Pneumothorax is a known risk factor for all patients requiring mechanical 
ventilation with a case rate of <1% of all mechanically ventilated patients. In 
previous studies of optimal PEEP determination using esophageal balloon-guided 
pressure measurement, no pneumothoraces were observed. We believe the study 
procedures will be safe for both arms, and that the intervention arm will be at lower 
risk for this outcome. However, development of a pneumothorax will necessitate a 
chest tube and will invalidate the measurement of pleural pressure. Therefore the 
study procedures must be stopped. 
• Epistaxis requiring intervention 
o In the event of epistaxis requiring packing or intervention, the esophageal balloon 
will be removed and the study subject’s participation in the study will end. 
• Hypotension 
o In the event a patient experiences a drop in mean arterial pressure (MAP) below 
65 mm Hg or a significant change in vasoactive medication requirement (>10 
mcg/min dose of norepinephrine equivalent), that is felt by the clinical ICU team to 
possibly be related to the intervention, the study subject’s PEEP will be dropped 
by 2 cm H2O every 5 minutes until the parameter returns to an acceptable range 
(as determined by the clinical ICU team) or until the PEEP reaches the pre-
intervention level. The patient will remain on no higher than this new PEEP for the 
remainder of the study.  
Adverse Event Reporting 

15 
Master Protocol: Optimal PEEP for Prevention of VILI 
All Adverse Events will be documented and graded using CTCAE grading, defined as any patient 
who develops one of the following (by CTCAE grading): 
• grade 3-5 hypotension  
• grade 2-5 pneumothorax 
• grade 2-5 epistaxis 
Screening for possible adverse events will occur daily. Each possible adverse event will be 
reviewed by a UNC critical care physician, independent of the study, within 72 hours of 
occurrence. The primary independent reviewer will be Adrian Austin, MD, MSCR; if he is on 
clinical service responsible for the study subject, then Jason Mock, MD, PhD will serve as the 
independent reviewer. After independent review, events considered to be probably or definitely 
related to the intervention will be submitted to the IRB for review. In addition, we will utilize a 
Data and Safety Monitoring Board to review aggregate safety data. 
7.3 
Data and Safety Monitoring Board (DSMB) 
We will utilize the NC TraCS DSMB for additional regulatory monitoring of the study. The DSMB 
will review aggregate safety data after enrollment of 25, 50, and 75% of the study participants. 
There will be several criteria for evaluating safety and possible early stopping of the trial. Adverse 
events will be graded based on the CTCAE criteria listed above (7.2 AE Reporting). 
1) Pneumothorax – If 2 out of 10, or if more than 10 enrolled, 20% out of enrolled subjects 
experience pneumothorax, then the study will be suspended until the DSMB can review 
the information and provide recommendations. 
2) Hypotension – If 2 out of 10, or if more than 10 enrolled, 20% out of enrolled subjects 
experience refractory hypotension, then the study will be suspended until the DSMB can 
review the information and provide recommendations. 
3) Death – If 8 out of 10, or if more than 10 enrolled, 60% out of enrolled subjects die, then 
the study will be suspended until the DSMB can review the information and provide 
recommendations. 
There are no stopping rules for efficacy, as there will be no interim efficacy analyses. The 
study is only adequately powered to detect an efficacy difference if it were completed. 
8 
DATA COLLECTION AND MANAGMENT  
All patient data will be collected using UNC REDCap through the NC TraCS system. REDCap 
allows for immediate data validation and range setting to reduce the likelihood of erroneous data 
entry. Data created for analysis will be de-identified and secured on a password protected UNC 
School of Medicine network hard drive. All investigators will be trained on completing the 
electronic case report form. 
 
All data will be recorded on computerized case report forms via REDCap, which will be transferred 
(after de-identification, as follows) to a centralized database constructed and operated for this project 
by the UNC TraCS Clinical Research Data Management Service.  This database system provides for 
secure web-based data entry with the data stored on servers that we maintain.  The data is encrypted 
during transmission.  The servers are located in a secure campus area with all the appropriate physical 
security measures in place.  One ITS group manages the space where the servers are housed, but that 

16 
Master Protocol: Optimal PEEP for Prevention of VILI 
team does not have access or manage content on the servers.  UNC-Chapel Hill’s TraCS IT staff (a 
team of 5 and the research team will have access to data collected in this study, as standard for most 
University server spaces.  Research teams are provided access at the user level, per site. Only the 
investigators and project manager will have access to aggregate data. The data is encrypted during 
transmission using industry standards of TSL 1.1 algorithms (including MD5, AES, etc). The web and 
database servers are monitored by the TraCS IT staff, patched frequently, and scanned by a third party 
vendor to ensure that they are protected against known vulnerabilities.  The scanning application is the 
standard service for the entire campus.  Access is by individual user id with User-level permissions that 
define only those records an individual is authorized to see and is restricted to the forms and/or 
functions that the user needs to have.  The applications themselves are written using open source 
tools, and have also been scanned by campus security office to ensure that the applications also are 
protected from known exploits.  The data is backed up to electronic media on a daily basis.  The 
electronic media is secured by ITS stored in a secure area separate from the servers.  
The UNC TraCS Clinical Research Data Management Service endeavors to preserve the privacy, 
confidentiality, and security of protected health information that may be part of health records or 
research datasets. Protected Health Information (PHI) is handled according to appropriate Health 
Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy and Security Regulations. Staff 
who work with PHI are required to complete appropriate HIPAA and other compliance training in 
accordance with institution policy.  
 
  
9 
RECRUITMENT STRATEGY 
Potential participants will be identified from daily screening of intubated patients in the MICU of 
each study site by research personnel. After identification of potential participants, study team 
members will approach the critical care team for confirmation of appropriateness and permission 
to enroll participants. If the clinician is agreeable, a study team member will approach the legally 
authorized representative for explanation of the study.  
The patients’ decision-making surrogates will be primarily approached to consent for 
participation in this study as most mechanically ventilated patients are medically or clinically 
sedated and not able to have decision making capacity. The investigators and/or research 
coordinators will approach the surrogates individually after the patients are identified as being 
eligible for the study to provide an informed consent process. Full disclosure will be provided 
that enrollment in this study will be optional and not affect major treatment decisions. 
10 
CONSENT PROCESS 
The recruitment team will approach the patient’s legal next of kin. These conversations will occur 
in the patient care room of the intensive care unit or a private consultation room in/near the 
intensive care unit with a trained study team member. Study information will be reviewed with 
the patient’s next of kin and a copy of the IRB approved consent form will be provided for review. 
After having the chance to consider the trial, a time will be scheduled for the consent process. 
For patients whom no legal next of kin is physically present, the study team will make contact 
via telephone. In instances where inpatient consenting is not possible, e-consentingmay be 
utilized per institutional and IRB approved guidelines.  
Cognitive impairment is a common symptom of critical illness and mechanical ventilation. 
Patients requiring mechanical ventilation are also frequently given psychoactive medications 

17 
Master Protocol: Optimal PEEP for Prevention of VILI 
(sedatives and analgesics) for sedation and comfort. Due to these circumstances, consent from 
an appropriately informed legally authorized representative (LAR) will be used for any patient 
who is cognitively unable to consent for any reason upon examination by research staff. 
Screening for cognitive impairment during screening and enrollment will entail the administration 
of a CAM-ICU, orientation questions or other approved methods per institutional or IRB 
guidelines. Cognitive impairment confirmation should be documented by research staff in 
enrollment notes. Consideration of appropriate LAR will be given in order of descending priority 
as identified by respective State law. Consent will be obtained by the study personnel in a private 
area.  
Research staff may be introduced to family members at the bedside by the ICU physician or will 
call the next of kin if family is not available at the bedside. The Legally Authorized Representative 
(LAR) will be identified and consented for enrollment. The LAR may be a family member or 
surrogate in order of priority or someone who holds valid power of attorney documentation. All 
subjects will be informed that research is voluntary and refusal does not jeopardize their medical 
care or university status in any kind of way. Research subjects will be followed according to 
HIPAA guidelines. 
Patients will be followed for recovery of cognitive function, and they will undergo the same 
informed consent process during reconsent if/when they are able during the hospitalization.  
 
11 
PLANS FOR PUBLICATION 
At the conclusion of the study, the data will be analyzed and reported in manuscript form for 
submission to relevant pulmonary and critical care journals, including but not limited to American 
Journal of Respiratory and Critical Care Medicine, Chest, Critical Care, and Journal of Critical 
Care. Data will also be used for further grant applications. 
 
12 
REFERENCES  
1. 
Bilek AM, Dee KC, Gaver DP. Mechanisms of surface-tension-induced epithelial cell damage in 
a model of pulmonary airway reopening. J Appl Physiol 2003;94:770–783. 
2. 
Bohm SH, Thamm OC, von Sandersleben A, Bangert K, Langwieler TE, Tusman G, Strate TG, 
Standl TG. Alveolar Recruitment Strategy and High Positive End-Expiratory Pressure Levels Do 
Not Affect Hemodynamics in Morbidly Obese Intravascular Volume-Loaded Patients. Anesth 
Analg 2009;109:160–163. 
3. 
Talmor DS, Fessler HE. Are esophageal pressure measurements important in clinical decision-
making in mechanically ventilated patients? Respir Care 2010;55:162-172; discussion 172-174. 
4. 
Talmor D, Sarge T, OʼDonnell CR, Ritz R, Malhotra A, Lisbon A, Loring SH. Esophageal and 
transpulmonary pressures in acute respiratory failure*. Crit Care Med 2006;34:1389–1394. 
5. 
Talmor D, Sarge T, Malhotra A, O’Donnell CR, Ritz R, Lisbon A, Novack V, Loring SH. 
Mechanical Ventilation Guided by Esophageal Pressure in Acute Lung Injury. N Engl J Med 
2008;359:2095–2104. 
6. 
Behazin N, Jones SB, Cohen RI, Loring SH. Respiratory restriction and elevated pleural and 

18 
Master Protocol: Optimal PEEP for Prevention of VILI 
esophageal pressures in morbid obesity. J Appl Physiol 2010;108:212–8. 
7. 
Obi ON, Mazer M, Bangley C, Kassabo Z, Saadah K, Trainor W, Stephens K, Rice PL, Shaw R. 
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Fish E, Novack V, Banner-Goodspeed VM, Sarge T, Loring S, Talmor D. The Esophageal 
Pressure-Guided Ventilation 2 (EPVent2) trial protocol: a multicentre, randomised clinical trial of 
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Patel BM, Chittock DR, Russell JA, Walley KR. Beneficial effects of short-term vasopressin 
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10. 
NIH. Common terminology criteria for adverse events v5.0. UpToDate 
2017;doi:10.1080/00140139.2010.489653. 
Appendix – Tables 
12.1 ARDSNet PEEP/FiO2 table