Evaluating Safety of Transpulmonary Pressure Guided PEEP Management in Neurocritical Care Patients
Phase: NA
Conditions: Respiratory Failure, Intracranial Hypertension
Sponsor: University of North Carolina, Chapel Hill

 
Evaluating the Safety of Transpulmonary Pressure Guided Optimal 
PEEP in Neurocritical Care Patients 
 
 
 
 
NCT number NCT03862027 
Document Date 04/09/2019 
 

1 
Master Protocol: Safety of Optimal PEEP in NSICU Patients 
Safety of Optimal PEEP in NSICU Patients: Master Protocol 
 
Complete Title:  
 
Evaluating the Safety of Transpulmonary Pressure Guided Optimal PEEP 
in Neurocritical Care Patients 
 
 
 
Short Title:  
 
Safety of Optimal PEEP in NSICU Patients 
Protocol Date: 
 
August 24, 2018 
Amendment 1 Date: 
November 5, 2018 
Amendment 2 Date:  
April 9, 2019 
Amendment 3 Date: 
Amendment 4 Date:  
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
Dustin Norton, MD 
CB# 7020, 130 Mason Farm Rd 
4th Floor Bioinformatics Bldg 
Chapel Hill, NC 27599 
Phone: 919-966-2533 
Email: dustin.norton@unchealth.unc.edu 
 
Faculty Advisor: 
Thomas Bice, MD MSc 
 
Co-Investigators:  
Dedrick Jordan, MD PhD 
Thomas Devlin, RT 
Agathe Ceppe, BS 
Amanda Kovacich, MD MPH 
 
 

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Master Protocol: Safety of Optimal PEEP in NSICU Patients 
TABLE OF CONTENTS 
Table of Contents .................................................................................................... 2 
Abbreviations and Definitions of Terms ............................................................... 3 
Protocol Synopsis .................................................................................................. 4 
1 
BACKGROUND  AND RATIONALE ............................................................................................... 7 
2 
STUDY OBJECTIVES .................................................................................................................... 8 
3 
INVESTIGATIONAL PLAN ............................................................................................................. 8 
4 
STUDY PROCEDURES ................................................................................................................. 9 
5 
STUDY EVALUATIONS AND MEASUREMENTS ....................................................................... 10 
6 
STATISTICAL CONSIDERATIONS .............................................................................................. 10 
9 
SAFETY MANAGEMENT ............................................................................................................. 11 
10  DATA COLLECTION AND MANAGEMENT ................................................................................. 11 
11 RECRUITMENT STRATEGY ....................................................................................................... 11 
12 CONSENT PROCESS .................................................................................................................. 12 
13 PUBLICATION .............................................................................................................................. 12 
14 REFERENCES .............................................................................................................................. 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Master Protocol: Safety of Optimal PEEP in NSICU Patients 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
PEEP 
Positive end expiratory pressure 
MV 
Mechanical ventilation 
VILI 
Ventilator induced lung injury 
ARDS 
Acute respiratory distress syndrome 
ICP 
Intracranial pressure 
CPP 
Cerebral perfusion pressure 
CT 
Computed tomography 
HR 
Heart rate 
BP 
Blood pressure 
FiO2 
Fraction of inspired oxygen 
SpO2 
Peripheral oxygen saturation 
Pes 
Esophageal Pressure 
Paw 
Airway pressure 
Ptp 
Transpulmonary pressure 
NSICU 
Neurosurgical intensive care unit 
CVP 
Central venous pressure 
MAP 
Mean arterial pressure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

4 
Master Protocol: Safety of Optimal PEEP in NSICU Patients 
PROTOCOL SYNOPSIS 
Study Title 
Evaluating the Safety of Optimal PEEP in Neuro Critical Care 
Patients 
Funder 
Departmental funds 
Study Rationale 
The use of positive end expiratory pressure (PEEP) in 
mechanical ventilation (MV) 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. There is a patient-
specific response to PEEP titration, but PEEP titration is 
frequently not guided by individual patient data. There is a 
growing body of evidence that titrating PEEP according to 
estimated transpulmonary pressure (Ptp) measurements 
obtained by an esophageal balloon can improve outcomes, 
including measurements of lung function and time to liberation 
from tracheostomy in obese patients requiring prolonged 
mechanical ventilation, but also with trends toward decreased 
mortality and less time on the ventilator in survivors of ARDS. 
Notably, these trials have excluded patients with elevated 
intracranial pressure (ICP) or conditions where hypercapnia-
induced elevations in intracranial pressure should be avoided 
[including intracranial bleeding, cerebral contusion, cerebral 
edema, mass effect (midline shift on CT scan), flat EEG for ≥2 
h] for theoretical concerns of increasing ICP and decreasing 
cerebral perfusion pressure (CPP). Contrary to these 
concerns, 
small 
studies 
have 
shown 
that 
cerebral 
autoregulation is improved or unchanged while increases in 
intracranial pressure are small or nonexistent with increases in 
PEEP. Additionally, one case cohort study showed improved 
hypercapnia with use of esophageal balloon to guide PEEP. 
This study seeks to evaluate the safety of titrating PEEP to 
“optimal PEEP” based on Ptp as measured by an esophageal 
balloon in patients requiring mechanical ventilation who have 
CPP or ICP monitoring in place to correlate titrated PEEP with 
changes in ICP. 
Study Objective(s) 
To evaluate the safety of PEEP titration using esophageal 
balloon guided estimates of Ptp in neuro critical care patients. 
Study Design 
 
Non-inferiority trial comparing the effects of titrated PEEP 
compared to standard PEEP management on ICP, CPP, and 
hemodynamics in neurocritical care patients. All enrolled 
patients 
will 
have 
esophageal 
balloons 
placed 
with 
measurement of Ptp before and after intervention as well as 
baseline measurements of ICP, CPP, and MAP. All patients will 
undergo titration of PEEP based on Ptp measurements to an 
“ideal PEEP” (defined as end expiratory Ptp of 0-2). 
Measurements of ICP, and CPP, and MAP will be taken 5 

5 
Master Protocol: Safety of Optimal PEEP in NSICU Patients 
minutes after the titration of PEEP to evaluate the effect of 
PEEP titration on ICP, CPP, and MAP.  
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria:  Adults (age ≥ 18) admitted to the Neuro ICU 
of UNC Hospital requiring mechanical ventilation and with 
intracranial pressure monitoring in place. 
Exclusion Criteria: 
1. Pneumothorax or pneumomediastinum 
2. Life expectancy < 24 hours or expected to require 
mechanical ventilation for < 24 hours 
3. Condition that precludes placement of an esophageal 
balloon (esophageal or nasopharyngeal pathology 
preventing insertion of the esophageal balloon 
catheter, severe thrombocytopenia or coagulopathy) 
4. Pre-enrollment ICP > 20 mg Hg or refractory ICP 
elevation necessitating current pharmacological 
treatment 
5. Pre-enrollment CPP < 60 mm Hg 
6. Planned change in the external ventricular drain set 
point during the pre-intervention, intervention or post-
intervention periods 
7. Pregnancy 
8. Incarceration 
9. Variation in ICP > 2 cm H2O in the 15 minutes prior to 
intervention. 
Number Of Subjects  
Approximately 25 subjects 
Study Duration 
Each subject’s participation will last 1 hour. The entire study is 
expected to last 12 months. 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
(1) Screening: Screening for eligibility and obtaining consent  
(2) Pre-Intervention: Baseline data collected, including ICP 
monitoring every 5 minutes for 15 minutes prior to the 
intervention to insure patients are at a steady state as it 
pertains to cerebral pressures. Patients with minimal ICP 
variation will then have an esophageal balloon placed to 
measure transpulmonary pressure. 
(3) Intervention: PEEP titrated to “optimal PEEP” based on Ptp 
(4) Post-Intervention: Data collection five minutes after 
intervention.  
(5) Subject Completion/Withdrawal: Ventilator management 
will be returned to the primary critical care team to determine 
PEEP going forward. In patients who continue on the titrated 
level of PEEP, safety data will be collected for an additional 24 
hours. 
Efficacy/Safety 
Evaluations 
This study is will use endpoints of ICP, CPP, and MAP to 
assess the safety of PEEP titration by Ptp measurements via 

6 
Master Protocol: Safety of Optimal PEEP in NSICU Patients 
esophageal balloon. Determination of safety will be made 
based on the lack of a clinically significant increase in ICP, 
decrease in CPP, or decrease in MAP. All patients will have 
continuous hemodynamic and oxygenation monitoring, in 
addition to ICP/CPP monitoring, per NSICU protocol to monitor 
patient safety. In patients who continue on the titrated level of 
PEEP after the intervention (decision made by the primary 
critical care team), ICP, CPP, hemodynamic, and oxygenation 
data will be recorded for 24 hours after the intervention to 
evaluate for any possible adverse events, and this data will also 
be reported. 
Statistical and 
Analytic Plan 
The trial is an interrupted time-series design non-inferiority trial 
evaluating “optimal PEEP” as determined by an esophageal 
balloon compared to baseline standard PEEP management. 
The primary outcome will be intracranial pressure with a non-
inferiority limit of 4 mm Hg, analyzed with a non-inferiority 
design. CPP and MAP are secondary outcomes with non-
inferiority margin of 10 mm Hg each. 
DATA AND SAFETY 
MONITORING PLAN 
The PI and Faculty Mentor 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.  At the conclusion of the 
intervention, PEEP management will be returned to the primary 
clinical team. In patients who remain on the titrated level of 
PEEP, clinical information will be reviewed for 24 hours to 
identify and report any possible adverse events. 
 
 
 
 
 
 
 
 
 

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Master Protocol: Safety of Optimal PEEP in NSICU Patients 
1 
BACKGROUND AND RATIONALE 
1.1 
Introduction 
This is an interrupted time-series design, non-inferiority trial to evaluate the safety of “optimal 
PEEP” in mechanically ventilated neurocritical care patients at UNC Hospital. 
1.2 
Description of Intervention  
Trial participants will have placement of an esophageal balloon with manometry capabilities. 
Baseline measurements of Ptp, ICP, CPP, and MAP will be made at their baseline PEEP 
measurement. All patients will then undergo titration of PEEP based on Ptp measurements to an 
“ideal PEEP” with end expiratory Ptp of 0-2. Measurements of ICP, CPP, and MAP will be taken 
5 minutes after the intervention. Data will be compared before and after intervention. At the 
conclusion of the intervention, PEEP management will return to the primary team. In patients 
continued on the “optimal” level of PEEP, patient data will be monitored for an additional 24 
hours in order to report any possible adverse events. 
1.3 
Background (Relevant Literature and Data) 
The use of PEEP in mechanical ventilation (MV) 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. There is a growing body of evidence 
that titrating PEEP according to estimated transpulmonary pressure (Ptp) measurements 
obtained by an esophageal balloon can improve outcomes, including measurements of lung 
function and time to liberation from tracheostomy in obese patients requiring prolonged 
mechanical ventilation, but also with trends toward decreased mortality and less time on the 
ventilator in survivors of ARDS (2-4). These trials, as well as an ongoing multicenter trial using 
an esophageal balloon to titrate PEEP in patients with ARDS, have excluded patients with 
elevated intracranial pressure (ICP) or conditions where hypercapnia-induced elevations in 
intracranial pressure should be avoided [including intracranial bleeding, cerebral contusion, 
cerebral edema, mass effect (midline shift on CT scan), flat EEG for ≥ 2 h] for theoretical 
concerns of increasing ICP and decreasing cerebral perfusion pressure (CPP) (5). Contrary to 
these concerns, small studies evaluating use of PEEP in this patient population have shown that 
cerebral autoregulation is improved or unchanged while increases in ICP are small or 
nonexistent (6-10). Increases in PEEP without guidance of an esophageal balloon in one study 
caused a clinically insignificant rise in ICP in patients with normal ICP at baseline, however 
patients with elevated ICP (> 15 mm Hg) at baseline saw no increase in ICP as PEEP was 
increased (11). Additionally, one case cohort study showed improved hypercapnia with use of 
esophageal balloon to guide PEEP (3).  
This protocol seeks to evaluate the safety of titrating PEEP to “optimal PEEP” based on Ptp as 
measured by and esophageal balloon in patients requiring MV who have CPP or ICP monitoring 
in place. 
 
 

8 
Master Protocol: Safety of Optimal PEEP in NSICU Patients 
2 
STUDY OBJECTIVE  
The purpose of the study is to evaluate the safety of esophageal-pressure-guided PEEP 
management in neuro critical care patients. 
2.1 
Primary Objective 
To determine that titration of PEEP to optimal PEEP does not result in clinically significant 
changes in ICP (defined as an increase in ICP > 4 mm Hg). 
2.2 
Secondary Objectives 
a. To determine that titration of PEEP to “optimal PEEP” does not result in clinically significant 
changes in CPP (defined as an increase in CPP > 10 mm Hg. 
b.  To determine that titration of PEEP to “optimal PEEP” does not result in clinically significant 
changes in MAP (defined as a decrease in MAP > 10 mm Hg. 
c. To report any possible adverse events after titration of PEEP.  
 
3 
INVESTIGATIONAL PLAN  
3.1 
Study Design 
Noninferiority trial 
3.2 
Study Duration, Enrollment and Number of Subjects 
Enrollment will continue until 18 subjects have been enrolled who require an increase in PEEP 
of at least 5 cm H20 (based on Ptp at the time of enrollment). Based on a prior study which found 
29% of participants were within 5 cm H2O of optimal PEEP at the time of enrollment (2), we 
expect we will need to measure esophageal pressures on approximately 25 patients to find 18 
patients who require titration of PEEP. Based on expected enrollment of 2-4 participants per 
month, the trial is expected to complete enrollment within 12 months. Each patient’s participation 
will last 1 hour; for the few patients who remain on higher PEEP per the request of the team, 
safety monitoring will continue for an additional 24 hours. 
3.3 
Study Population 
Inclusion Criteria:  Adult patients (age ≥ 18) admitted to the Neuro ICU of UNC Hospital requiring 
mechanical ventilation and with ICP monitoring in place. 
 
Exclusion Criteria: 
1. 
Pneumothorax or pneumomediastinum 
2. 
Life expectancy < 24 hours or expected to require mechanical ventilation for < 24 hours 
3. 
Condition that precludes placement of an esophageal balloon (esophageal or 
nasopharyngeal pathology preventing insertion of the esophageal balloon catheter, 
severe thrombocytopenia or coagulopathy) 
4. 
Pre-enrollment ICP > 20 mm Hg 
5. 
Pre-enrollment CPP < 60 mm Hg 
6. 
Planned change in the external ventricular drain set point during the pre-intervention, 
intervention or post-intervention periods 
7. 
Pregnancy 
8. 
Incarceration 
9. 
Variation in ICP of > 2 cm H2O in the 15 minutes prior to intervention. 
 
 

9 
Master Protocol: Safety of Optimal PEEP in NSICU Patients 
4 
STUDY PROCEDURES 
4.1 
Screening/Enrollment 
Daily screening of all intubated patients in the Neurosurgery ICU will be conducted by the 
research team. Intubated patients will be evaluated for the presence of ICP monitors. For 
patients meeting these criteria, chart review will be performed to evaluate for exclusion criteria. 
The primary clinical team will then be approached for permission to enroll prior to approaching 
families of patients for enrollment. 
4.2 
Pre-Intervention 
All patients will have an esophageal balloon catheter 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 – 20 cm 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 [Esophageal Pressure (Pes), Airway Pressure (Paw), and Transpulmonary Pressure 
(Ptp)] are measured directly through the ventilator. The waveforms of Paw, Pes, and Ptp will be 
visualized on the ventilator. Ptp is obtained from Paw – Pes. All patients will have baseline 
measurements recorded of ICP, CPP, HR, and MAP. 
4.3 
Intervention  
PEEP will be increased on the ventilator to achieve a Ptp between 0 and +2 cm H2O (“Optimal 
PEEP”). 
4.4 
Post-Intervention 
Measurements of ICP, CPP, and MAP will be repeated 5 minutes after the change in PEEP. 
4.5 
Subject Completion/ Withdrawal 
At the conclusion of the intervention, the trial will be completed. Ventilator management will be 
returned to the primary critical care team who will determine PEEP level going forward. In 
patients who are maintained thereafter on the “optimal PEEP”, safety data will be collected for 
an additional 24 hours. 
 
 
 

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Master Protocol: Safety of Optimal PEEP in NSICU Patients 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
  
  
Pre-Intervention 
Post-Intervention 
Hourly x 24 Hours* 
ICP 
x 
x 
x 
CPP 
x 
x 
x 
MAP 
x 
x 
x 
HR 
x 
x 
x 
SpO2 
x 
x 
x 
FiO2 
x 
x 
x 
PEEP 
x 
x 
x 
Ptp 
x 
x 
  
Paw 
x 
x 
  
Pes 
x 
x 
  
Age 
x 
  
  
BMI 
x 
  
  
Diagnosis 
x 
  
  
*Hourly data collected in patients who are continued on "optimal PEEP at the discretion of the 
primary team. 
 
 
 
6 
STATISTICAL CONSIDERATION    
6.1 
Primary Endpoint 
The primary endpoint is change in ICP 5 minutes after PEEP titration. the parameter 
representing mean increase during/after titration is > 4 (mm Hg) in the target population. 
6.2 
Secondary Endpoints 
1. CPP before and after intervention. 
2. MAP before and after intervention. 
3. Adverse events will be evaluated by the frequency, type, and severity, and these data will be 
reported  
6.3 
Statistical Methods 
All endpoints will be described in term of means and standard deviation, with associated 95% 
confidence intervals, and median [Q1-Q3] 
The change in ICP will be analyzed with a non-inferiority study: the ICP value after intervention 
will be considered equivalent to the ICP before intervention if the 95% upper bound of the change 
is lower than the non-inferiority margin of 4 mm Hg.  
In a similar manner, the CPP and MAP values before and after intervention will be considered 
equivalent if the 95% lower bounds of the respective changes are higher than -10 mm Hg.   
Should the 95% upper bounds of ICP be higher than 4, the effect of the intervention would be 
considered inconclusive. Similarly if the equivalence of CPP and MAP cannot be observed, the 
intervention will be reported inconclusive for these endpoints.  
Adverse events will be reported. 

11 
Master Protocol: Safety of Optimal PEEP in NSICU Patients 
By study design, all patients will be monitored in the ICU for the duration of the study and missing 
values are not expected. However, in the unlikely event that missing values would be present, 
the subjects will not be excluded and statistics will be calculated on all available data. The 
dataset for analysis will consist of all subjects regardless of protocol deviation, as an Intent-to-
treat population. 
Additional data points from the table above will be collected and tabulated using mean and 
standard deviation. 
 
6.4 
Sample Size and Power 
Based on a non-inferiority trial design using a one-sided 95% confidence interval, a power of 
80%, a non-inferiority limit of 4 mm Hg for ICP, and a standard deviation of 4.4 mm Hg based 
on previously published data (11), the study will need 15 participants who require a change in 
PEEP based on esophageal balloon measurements. To evaluate our secondary goals, using a 
non-inferiority limit of 10 mm Hg for CPP and a standard deviation of 11.3, we would need 16 
subjects, and using a non-inferiority limit of 10 mm Hg for MAP and a standard deviation of 11.8, 
we would need 18 subjects.  
Since we estimate that 29% will not need a change in PEEP (2), we expect we will need to enroll 
25 participants and obtain esophageal balloon pressure measurements in order to have 18 
participants requiring changes in PEEP. 
 
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 minimal 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 barotrauma, 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 (2). 
7.2 
Safety Monitoring 
Data will be collected 5 minutes after the intervention, giving time for pressure equilibration from 
the ventilator and its effect on ICP, CPP, and MAP. Significant changes in these metrics, as 
defined above, will be reported as adverse events. At the conclusion of the intervention, PEEP 
management will be returned to the primary team. In patients whom they continue the “optimal 
PEEP” level, we will continue to evaluate for possible adverse events for an additional 24 hours, 
and this data will be reported. In addition to clinically significant changes in ICP, CPP, and MAP 
as defined above, additional adverse events that will be reported will include evidence of new 
barotrauma, change in pressor requirement,or change in HR to > 120 or < 50. 
7.3 
Adverse Event Reporting 
“Possible Adverse Event” will be defined as a patient meeting any of the above parameters. 
Each possible adverse event will be reviewed by a UNC critical care physician who is 
independent of the study within 72 hours. After independent review, events considered to be 
likely or definitely related to the intervention will be submitted to the IRB for review. 
 
8 
DATA COLLECTION AND MANAGMENT  

12 
Master Protocol: Safety of Optimal PEEP in NSICU Patients 
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. 
 
9 
RECRUITMENT STRATEGY 
Potential participants will be identified from daily screening of intubated patients in the NSICU 
by the study team. 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 family/next-of-
kin for explanation of the study. 
 
North Carolina General Statute 90‐21.13 for surrogate medical decision making to establish next 
of kin is as follows: 
a. 
Court‐appointed legal guardian (except to the extent any appointed health care agent has 
authority, unless the health care agent’s authority has been suspended by a court order). 
b. 
A health care power of attorney (HCPOA) may provide surrogate consent for research 
participation to the extent this does not contradict the written HCPOA. 
c. 
A durable general power of attorney, unless the research participation includes an activity 
expressly excluded from the power of attorney.  
d. 
In the event that there is neither a court appointed guardian nor an agent under a durable 
general power of attorney or HCPOA, surrogate consent for research may be given, as 
long as there is no evidence to the contrary, by the other individuals listed below, in order 
of priority: 
 
1. 
The subject’s spouse. 
 
2.  
A majority of the subject’s reasonably available parents and adult children. 
 
3. 
A majority of the subject’s reasonably available adult siblings. 
 
4. 
Another individual with an established relationship with the subject who is acting  
 
 
in good faith on behalf of the subject and can reliably convey the subject’s wishes. 
 
Protection of Human Subjects 
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 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. 

13 
Master Protocol: Safety of Optimal PEEP in NSICU Patients 
For patients whom no legal next of kin is physically present, the study team will make contact 
via telephone.  
 
11 
PLANS FOR PUBLICATION 
At the conclusion of the study, the data will be analyzed and reported in manuscript form for 
submission to relevant critical care and neurology journals, including but not limited to Chest, 
Critical Care, Neurocritical Care, and Journal of Critical Care. Data will also be used for further 
grant applications. 

14 
Master Protocol: Safety of Optimal PEEP in NSICU Patients 
REFERENCES  
1. 
Bilek AM, Dee KC, Gaver DP, 3rd. Mechanisms of surface-tension-induced epithelial cell damage in a model of 
pulmonary 
airway 
reopening. 
J 
Appl 
Physiol 
(1985). 
2003;94(2):770-83. 
Epub 
2002/11/16. 
doi: 
10.1152/japplphysiol.00764.2002. PubMed PMID: 12433851. 
2. 
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(20):2095-104. Epub 2008/11/13. doi: 
10.1056/NEJMoa0708638. PubMed PMID: 19001507; PMCID: PMC3969885. 
3. 
Soroksky A, Kheifets J, Girsh Solomonovich Z, Tayem E, Gingy Ronen B, Rozhavsky B. Managing hypercapnia in 
patients with severe ARDS and low respiratory system compliance: the role of esophageal pressure monitoring--a case 
cohort study. Biomed Res Int. 2015;2015:385042. Epub 2015/02/20. doi: 10.1155/2015/385042. PubMed PMID: 
25695069; PMCID: PMC4324110. 
4. 
Piraino T, Cook DJ. Optimal PEEP guided by esophageal balloon manometry. Respir Care. 2011;56(4):510-3. Epub 
2011/01/25. doi: 10.4187/respcare.00815. PubMed PMID: 21255501. 
5. 
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 mechanical ventilation guided by transpulmonary 
pressure. BMJ Open. 2014;4(9):e006356. Epub 2014/10/08. doi: 10.1136/bmjopen-2014-006356. PubMed PMID: 
25287106; PMCID: PMC4187996. 
6. 
Cooper KR, Boswell PA, Choi SC. Safe use of PEEP in patients with severe head injury. J Neurosurg. 1985;63(4):552-
5. Epub 1985/10/01. doi: 10.3171/jns.1985.63.4.0552. PubMed PMID: 3897477. 
7. 
Wolf S, Schurer L, Trost HA, Lumenta CB. The safety of the open lung approach in neurosurgical patients. Acta 
Neurochir Suppl. 2002;81:99-101. Epub 2002/08/10. PubMed PMID: 12168369. 
8. 
Lou M, Xue F, Chen L, Xue Y, Wang K. Is high PEEP ventilation strategy safe for acute respiratory distress syndrome 
after severe traumatic brain injury? Brain Inj. 2012;26(6):887-90. Epub 2012/05/16. doi: 10.3109/02699052.2012.660514. 
PubMed PMID: 22583180. 
9. 
Schramm P, Closhen D, Felkel M, Berres M, Klein KU, David M, Werner C, Engelhard K. Influence of PEEP on 
cerebral blood flow and cerebrovascular autoregulation in patients with acute respiratory distress syndrome. J Neurosurg 
Anesthesiol. 2013;25(2):162-7. Epub 2012/12/06. doi: 10.1097/ANA.0b013e31827c2f46. PubMed PMID: 23211642. 
10. 
De Rosa S, Villa G, Franchi P, Mancino A, Tosi F, Martin MA, Bazzano S, Conti G, Pulitano SM. Impact of positive 
end expiratory pressure on cerebral hemodynamic in paediatric patients with post-traumatic brain swelling treated by 
surgical decompression. PLoS One. 2018;13(5):e0196980. Epub 2018/05/11. doi: 10.1371/journal.pone.0196980. PubMed 
PMID: 29746600; PMCID: PMC5944965. 
11. 
McGuire G, Crossley D, Richards J, Wong D. Effects of varying levels of positive end-expiratory pressure on 
intracranial pressure and cerebral perfusion pressure. Crit Care Med. 1997;25(6):1059-62. Epub 1997/06/01. PubMed 
PMID: 9201061.