Use of Electrical Impedance Tomography for Optimization of Positive End-Expiratory Pressure in Acute Respiratory Distress Syndrome
Phase: NA
Conditions: Acute Respiratory Distress Syndrome, ARDS
Sponsor: University of Michigan

 
 
 
 
 
Use of Electrical Impedance Tomography for 
Optimization of Positive End-Expiratory Pressure in 
Acute Respiratory Distress Syndrome 
Protocol Version V (January 16, 2020) 
 
   
NCT03793842 
 
 
 
 
 
 
 
 
 
PI: Robert C. Hyzy, MD  
Professor of Medicine 
Division of Pulmonary and Critical Care Medicine 
University of Michigan School of Medicine  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table of Contents 
 
TABLE OF CONTENTS .................................................................................................. 2 
ABBREVIATIONS........................................................................................................... 4 
DEFINITIONS ................................................................................................................. 5 
1 BACKGROUND ........................................................................................................... 6 
1.1 STUDY RATIONALE .............................................................................................. 7 
2 OBJECTIVES .............................................................................................................. 7 
2.1 PRIMARY OBJECTIVE ................................................................................................ 7 
2.2 SECONDARY OBJECTIVE ........................................................................................... 7 
2.3 PRIMARY HYPOTHESIS .............................................................................................. 7 
3 END POINTS ............................................................................................................... 8 
3.1 PHYSIOLOGIC ENDPOINTS ......................................................................................... 8 
3.2 BIOMARKER ENDPOINTS ............................................................................................ 8 
3.3 MONOCYTE ENDPOINTS ............................................................................................. 8 
4 STUDY POPULATION AND ENROLLMENT .............................................................. 8 
4.1 NUMBER/SOURCE/SCREENING................................................................................... 8 
4.2 INCLUSION CRITERIA ................................................................................................. 8 
4.3 EXCLUSION CRITERIA ................................................................................................ 9 
4.4 RANDOMIZATION, AND STUDY INITIATION TIME WINDOW .............................................. 9 
4.5 INFORMED CONSENT ................................................................................................. 9 
4.6 RANDOMIZATION ..................................................................................................... 10 
5 STUDY PROCEDURES ............................................................................................. 10 
5.0 STUDY DESIGN: ...................................................................................................... 10 
5.1. STUDY INITIATION .................................................................................................. 10 
5.1.2 MINI-BAL PROCEDURE ........................................................................................ 10 
5.1.3 USUAL CARE FIRST GROUP .................................................................................. 11 
5.1.4 ELECTRICAL IMPEDANCE TOMOGRAPHY (EIT) FIRST GROUP .................................. 11 
5.1.5 EIT PEEP TITRATION .......................................................................................... 12 
5.1.6 RESCUE PROCEDURES ......................................................................................... 13 
5.1.7 OTHER ASPECTS OF CARE ................................................................................... 13 
6 DATA COLLECTION ................................................................................................. 13 
6.1 BACKGROUND ASSESSMENTS ................................................................................. 13 

 
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6.2 BASELINE ASSESSMENTS ........................................................................................ 14 
6.3 ASSESSMENTS DURING STUDY ................................................................................ 14 
7 STATISTICAL CONSIDERATIONS ........................................................................... 16 
8 DATA COLLECTION ................................................................................................. 16 
9 RISK ASSESSMENT ................................................................................................. 16 
9.1 RISKS OF MINI-BAL ................................................................................................ 16 
9.2 RISKS OF HIGH PEEP ............................................................................................. 16 
9.3 RISK OF DEATH ...................................................................................................... 17 
9.4 MINIMIZATION OF RISKS .......................................................................................... 17 
9.5 POTENTIAL BENEFITS.............................................................................................. 17 
9.6 RISKS IN RELATION TO ANTICIPATED BENEFITS ........................................................ 17 
10 HUMAN SUBJECTS ................................................................................................ 18 
10.1 SELECTION OF SUBJECTS ...................................................................................... 18 
10.1.1 EQUITABLE SELECTION OF SUBJECTS ................................................................. 18 
10.2 INFORMED CONSENT ............................................................................................. 18 
10.3 WITHDRAWAL OF CONSENT ................................................................................... 19 
10.4 IDENTIFICATION OF LEGALLY AUTHORIZED REPRESENTATIVES ................................. 19 
10.5 JUSTIFICATION OF SURROGATE CONSENT .............................................................. 19 
10.6 ADDITIONAL SAFEGUARDS FOR VULNERABLE SUBJECTS ......................................... 20 
10.7 CONFIDENTIALITY ................................................................................................. 20 
11 ADVERSE EVENTS ................................................................................................. 20 
APPENDICES ............................................................................................................... 23 
A. Exclusion Definitions........................................................................................... 23 
B. Flowchart of Management of EIT Study Groups ............................................... 24 
C. ARDS Ventilator Management Strategies .......................................................... 25 
D. Drager Pulmovista 500 .............................................. Error! Bookmark not defined. 
E. EIT Studies ............................................................................................................ 28 
F. Time-Event Schedule ........................................................................................... 29 
G. Imputed PaO2/FiO2 ............................................................................................... 30 
H. SOFA Scoring System ......................................................................................... 31 
I. Recruitment Maneuver Policy (on file) ................................................................. 32 
REFERENCES .............................................................................................................. 33 
 
 

 
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ABBREVIATIONS 
 
ALI = Acute Lung Injury 
ARDS = Acute Respiratory Distress 
Syndrome 
BAL = Bronchoalveloar lavage 
BMI = Body Mass Index 
BUN = Blood Urea Nitrogen 
CHF = Congestive Heart Failure 
CPAP = Continuous Positive Airway 
Pressure 
Cst = Static compliance 
Cdyn = Dynamic compliance 
C20 = change in compliance over the last 
20% of inspiration 
CT = Computed Tomography 
DBP = Diastolic Blood Pressure 
DSMB = Data Safety Monitoring Board 
ECMO = Extracorporeal Membrane 
Oxygenation 
EIT = Electronic Impedance Tomography 
FiO2 = Fraction of Inspired Oxygen 
GCS = Glasgow Coma Scale 
IBW = Ideal body weight 
ICU = Intensive Care Unit 
IL-6 = Interleukin 6 
IL-8 = Interleukin 8 
INR = International Normalized Ratio 
LAR=legally authorized relative 
LTAC = Long Term Acute Care facility 
mBW = measured body weight 
OR = Odds Ratio 
P/F = PaO2/FiO2 ratio 
PaCO2 = Partial pressure of arterial carbon 
dioxide 
PaO2 = Partial pressure of arterial oxygen 
PAP = Pulmonary Artery Pressure 
PB = Barometric Pressure 
PBW = Predicted Body Weight 
PEEP = Positive End-Expiratory Pressure 
PI = Principal investigator 
PIN = Personal Identification Number 
Pmean = Mean airway pressure 
Ppeak= Peak airway pressure 
Pplat = Plateau pressure 
PS = Pressure Support Ventilation 
RASS = Richmond Agitation Severity Score 
SBP = Systolic Blood Pressure 
S/F = SpO2/FiO2 ratio 
SP-D = Surfactant protein D 
SpO2 = Oxygen Saturation 
sRAGE = Soluble Form of Receptor for 
Advanced Glycation End Products 
TNFR1 = Tumor necrosis factor receptor 1 
VAP = Ventilator-associated Pneumonia 
VFD = Ventilator-free Days 
VWF = Von Willebrand Factor 
WBC = White Blood Cell

 
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DEFINITIONS  
 
Controlled Ventilation: Any mode with a backup rate and which allows clinicians to 
either set tidal volume to a target or adjust pressures to target a tidal volume. Examples 
include volume assist control, pressure assist control, pressure regulated volume 
control. 
 
Study withdrawal: Defined as permanent withdrawal from study before completion of 
study activities. This does not include those subjects who have completed the protocol 
procedures or stopped procedures because they have reached unassisted breathing. If 
a patient or surrogate requests withdrawal from the study the clinician should seek 
explicit permission to continue data collection. 
 
Invasive Mechanical Ventilation: Assisted ventilation delivered by a nasotracheal, 
orotracheal, or tracheostomy tube 
 
Legal Representative: An individual, judicial, or other body authorized under applicable 
law to consent on behalf of a prospective patient to the patient's participation in the 
clinical study. 
 
Study Day: The day of randomization is study day zero.  The next day is study day one. 
 
 
 
 
 

 
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Use of Electrical Impedance Tomography for Optimization of 
Positive End-Expiratory Pressure in Acute Respiratory 
Distress Syndrome 
 
1 Background 
Acute respiratory distress syndrome (ARDS) is a common condition in the intensive 
care unit [1] which requires invasive mechanical ventilation. Because the administration 
of mechanical breaths from the ventilator can exacerbate lung injury, patients with 
ARDS are treated with lung protective ventilation (LPV), which entails providing a low 
tidal volume in order to maintain a plateau pressure under 30 cm H2O [2]. LPV 
decreases lung inflammation as a means of improving outcomes [2,3]. In ARDS, the 
distribution of delivered gas via mechanical ventilation is heterogeneous: there are 
areas of atelectatic lung which are not ventilated and this accounts for the refractory 
hypoxemia seen in ARDS.  
 
Efforts to recruit areas of atelectatic lung via the administration of a high positive end-
expiratory pressure (PEEP) have been employed in an attempt to further improve the 
outcome of patients with ARDS; but this has met with mixed results [4,5]. On a breath 
by breath basis, during mechanical ventilation with ARDS and PEEP some areas of the 
lung may become over-distended, ostensibly worsening lung injury, a phenomenon 
called tidal hyperinflation [6]. In addition, patients with ARDS receiving LPV can develop 
ventilator asynchrony which results in the intermittent development of potentially 
injurious large tidal volumes [7,8].  
 
In ARDS, there is also heterogeneity between patients: some patients respond to PEEP 
with recruitment of atelectatic lung regions and improvement in gas exchange while 
others do not [9]. Ideally, mechanical ventilation in ARDS patients would be 
individualized such that the right amount of airway pressure is applied to each patient, 
maximizing recruitment while avoiding potentially harmful over-distension and tidal 
hyperinflation. 
 
At present, it is unknown how to make the best tradeoff between lung recruitment and 
over-distension. The best work in this area has been performed utilizing CT scanning, a 
tool not routinely available to clinicians [9,10]. The work of Chiumello, using CT 
scanning, has suggested the best tradeoff among four different approaches to 
mechanical ventilation in ARDS is the PEEP table utilized in the Canadian LOVS trial 
[10,11].   
 
Electrical impedance tomography (EIT) offers an opportunity to evaluate regional lung 
ventilation at the patient’s bedside [12-14].  Although EIT has been utilized to assess 
the distribution of lung ventilation in ARDS patients, large clinical trials are lacking. 
Single-center pilot studies are insufficient to make a determination regarding whether 
ventilator optimization via EIT improves clinical outcomes. Lung protective ventilation 

 
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results in some mitigation of lung inflammation and can be a useful surrogate endpoint 
in smaller trials [3,15].  Bronchoalveolar lavage specimens obtained from intubated 
patients with ARDS are studied for biomarkers of lung inflammation which reflect the 
relative success or failure of different forms of mechanical ventilation to protect the lung 
from additional injury. 
 
1.1 STUDY RATIONALE 
To date, studies of EIT in ARDS patients have only assessed the distribution of 
ventilation and not whether lung inflammation is decreased. Our research goals are to 
assess markers of lung inflammation: IL-6, IL-8, TNFR1, sRAGE, SP-D, Angiopoentin-2, 
and VWF in conjunction with ventilator changes made in ARDS patients correlated with 
EIT in order to determine whether the optimization of mechanical ventilation may be 
achieved by this means.  
 
One arm of the protocol will have best PEEP determined by oxygenation response 
using a PEEP/FiO2 combination table, similar to the one used in the LOVS protocol 
[11]. A modified version of the LOVS’s table (High-PEEP) has been incorporated into 
the University of Michigan ARDS protocol. EIT findings will be determined but the 
bedside respiratory therapist will be blinded to the EIT findings during this arm of the 
protocol. Alternatively, in the second arm of the protocol, EIT will be used to determine 
the best PEEP – i.e. the PEEP level at which recruitment is maximized and over-
distension minimized. Lung inflammatory markers obtained at 6 hours post recruitment 
via EIT will be compared with markers obtained 6 hours after the time when PEEP had 
been guided by the High-PEEP table.  In addition, following crossover to the opposite 
group, biomarkers will be obtained after an additional 14 to 18 hours. 
 
2 Objectives 
2.1 Primary Objective 
• To compare the effect of EIT in patients with moderate to severe and severe 
ARDS for the optimization of PEEP titration with standard PEEP titration using 
the High-PEEP table on changes in relevant physiological and biomarker 
outcomes. 
 
2.2 Secondary Objective 
• The BAL fluid will be examined for the presence of monocytes to determine 
whether mini-BAL is an effective method for collecting this type of specimen for 
future research. 
 
2.3 Primary Hypothesis 
• The use of electrical impedance tomography (EIT) to titrate positive end-
expiratory pressure (PEEP) will result in less lung inflammation and better 
physiologic parameters than use of the High-PEEP table in patients with 
moderate to severe acute respiratory distress syndrome (ARDS). 
 

 
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3 End Points 
• The protocol duration is 24 hours. 
 
3.1 Physiologic Endpoints 
 PaO2 
 P/F ratio 
 Pplat 
 Driving pressure 
 Cst and Cdyn 
 C20/dyn 
 
3.2 Biomarker Endpoints 
 IL-6 
 IL-8 
 sRAGE 
 SP-D 
 Angiopoetin-2 
 VWF 
 
3.3 Monocyte Endpoints 
 Monocyte phenotyping for HLA-DR expression 
 Single cell confocal Raman microscopy of circulating and lung 
monocyte/macrophage 
 Unbias metagenomic RNA-Seq mRNA quantitation in BAL macrophages 
 
4 Study Population and Enrollment 
4.1 Number/Source/Screening 
The trial will accrue 20 patients over a 1 to 2 year interval. Patients will be recruited from 
the emergency departments and the critical care medicine unit (CCMU). The overall 
strategy is to screen and enroll early, every newly intubated, acutely ill medical patient, 
using clinically obtained blood gases.  
 
4.2 Inclusion Criteria 
1. Age > 18 years 
2. Endotracheal ventilation for < 1 week (168 hours) 
3. Presence of all of the following conditions for < 72 hours 
i. 
PaO2/FiO2 < 150 with PEEP > 5 cm H2O for > 30 min. 
OR, IF ABG NOT AVAILABLE 
SpO2/FiO2 ratio that is equivalent to a PaO2/FiO2 < 150 with PEEP > 8 cm 
H2O (Appendix G), and a confirmatory SpO2/FiO2 ratio between 1-6 hours 
after the initial SpO2/FiO2 ratio determination 
ii. 
respiratory failure not fully explained by cardiac failure or fluid overload 

 
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4. Bilateral opacities not fully explained by effusions, lobar/lung collapse, or 
nodules for < 1 week (168 hours) 
5. All criteria listed in (3) developed within 1 week of a known clinical insult or 
new or worsening respiratory symptoms 
 
The 72-hour enrollment time window begins when criteria 1-4 are met. Criteria may 
be met at either the University of Michigan Hospital or a referring hospital.  
 
4.3 Exclusion Criteria 
1. Lack of informed consent 
2. Known pregnancy 
3. ECMO 
4. Severe chronic respiratory disease requiring home oxygen therapy or 
ventilation   
5. Calculated BMI of greater than 50 
6. Severe chronic liver disease defined as a Child-Pugh score of 12-15 
7. Prior bone marrow transplantation or present chemotherapy induced 
neutropenia 
8. Expected duration of mechanical ventilation of < 48 hours 
9. Decision to withhold life-sustaining treatment  
10. Moribund patient not expected to survive 24 hours 
11. Diffuse alveolar hemorrhage from vasculitis 
12. Burns > 40% total body surface or burns on the thorax 
13. Unwillingness to utilize the ARDS Network 6 ml/kg IBW ventilation protocol 
14. Neurologic conditions with risk of intracranial hypertension 
15. ARDS criteria met for > 48 hours 
16. Contraindications to using EIT (Presence of a pacemaker or AICD, inability to 
place the belt (presence of surgical wounds dressing, thoracic or spinal cord 
trauma, recent thoracic surgery, etc), undrained pneumothorax or BPF) 
17. Platelet count < 50 K/uL 
 
See Appendix A for specific exclusion criteria definitions. 
 
4.4 Randomization, and Study Initiation Time Window 
All patients must be randomized within 72 hours of meeting inclusion criteria. The 
window for randomization begins at the time of meeting all inclusion criteria, regardless 
of patient location.  
 
4.5 Informed Consent 
Informed consent will be obtained from each patient or legally authorized representative 
(LAR) prior to enrollment in the trial.  No study procedures will be done prior to obtaining 
informed consent.  
 
Permission to approach patients and/or LARs will be requested from the attending 
physicians. All patients meeting inclusion criteria will be entered on a screening log. If 
the patient is not enrolled, the screening log will include information explaining why 

 
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enrollment did not occur (e.g., exclusion criteria, attending physician denial, patient 
refusal). 
 
4.6 Randomization 
Randomization assignment will be made via sealed envelopes.  Twenty envelopes have 
been prepared containing the randomization selection – ten stating “EIT first” and ten 
stating “Usual Care First.”  These envelopes have been shuffled and stored in a larger 
envelope.  After obtaining a signed and dated informed consent, a sealed envelope will 
be selected and opened to reveal the randomization assignment.   
 
5 Study Procedures 
5.0 Study Design:   
Single-center, prospective, 2-arm, unblinded, randomized, cross-over clinical trial.   
 
5.1. Study Initiation  
At the time of randomization all study subjects will be receiving the standard University 
of Michigan ARDS protocol high PEEP arm (Appendix B).  All patients will receive lung 
protective ventilation (LPV), attempting to achieve a plateau pressure (Pplat) < 30 cm 
H2O with tidal volume by ideal body weight being allowed as high as 8 cc/kg and as low 
as 4 cc/kg in so doing. 
 
Following randomization patients will undergo a mini-BAL according the methodology 
undertaken by Ranieri and colleagues [16] prior to institution of the protocol arm.  
 
5.1.2 Mini-BAL Procedure 
After the administration of sedation, consisting of an increase in the baseline amount of 
propofol or midazolam already being administered, local anesthesia will be administered 
by instilling 1-3 cc aliquots of 2% lidocaine via the endotracheal tube port.  The use of 
local anesthesia is optional and will only be administered if deemed necessary by the 
clinician or RT. 
 
1. FiO2 will be increased to 1.0 ten (10) minutes prior to the start of the procedure. 
• Mini-BAL will not be performed if the P/F ratio is < 100 or the imputed S/F 
(Appendix G) ratio is less than 89. [17] 
• Mini-BAL will not be performed if the platelet count < 50 K/uL. 
2. Sedation with appropriate increases in propofol or midazolam will be made prior 
to insertion of the catheter.  
3. When diffuse infiltrates are seen on chest radiography, the mini-BAL catheter will 
be directed toward the right middle or lower lobes. When an area of localized 
pulmonary infiltrate is present the mini-BAL catheter will be directed toward the 
lower lobe of the opposite lung.  
4. A Halyard mini-BAL catheter will be inserted into the endotracheal tube and 
blindly advanced to the area noted above in #3. 

 
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5. Lavage with two aliquots of 40 cc sterile isotonic saline will be performed.  Fluid 
from the first aliquot will be discarded. 
6. A third lavage will be performed if less than 30 cc is recovered from the first two 
aliquots. 
7. The procedure will be terminated for a saturation <89% for >1 minute following 
the administration of any aliquot.  
8. The non-discarded BAL fluid will be put on ice and transported to Dr. Standiford’s 
laboratory for cytokine for IL-6, IL-8, TNFR1, sRAGE, SP-D, Angiopoentin-2, and 
VWF. 
 
5.1.3 Usual Care First Group 
1. Following completion of the initial mini-BAL, patients in the Usual Care First 
group will continue to receive mechanical ventilation according to the University 
of Michigan ARDS protocol High-PEEP arm (Appendix C).  Confirmation will be 
made to assure compliance with the High-PEEP table. 
2. Approximately six hours after randomization a second mini-BAL will be 
performed (5.1.2 above). 
3. Following completion of the second mini-BAL procedure Usual Care First 
patients will crossover and receive PEEP titration by EIT (see 5.1.5 below) for an 
additional 14-18 hours at which time a third mini-BAL will be performed.  The 
protocol will end after the third mini-BAL has been performed and the patient will 
return to mechanical ventilation PEEP titration via the University of Michigan 
ARDS protocol high PEEP arm.  All ventilator management will return to the 
clinical team. 
 
5.1.4 Electrical Impedance Tomography (EIT) First Group 
1. Following completion of the initial mini-BAL, patients in the EIT first group will 
have best PEEP determined by EIT (see 5.1.5 below).   
2. Approximately six hours after randomization a second mini-BAL will be 
performed (5.1.2 above). 
3. Between initial PEEP setting and the 2nd mini-BAL, ventilator management will 
follow the University of Michigan ARDS protocol, with the exception that PEEP 
will be left at the EIT determined level and only FiO2 adjusted for oxygenation 
issues.  If FiO2 reaches 1.0, the clinical team will use their discretion to manage 
PEEP. 
4. Following completion of the second mini-BAL procedure EIT first patients will 
crossover and receive PEEP titration by the University of Michigan ARDS 
treatment protocol using the high PEEP table for an additional 14-18 hours at 
which time a third mini-BAL will be performed.  The protocol will end after the 
third mini-BAL has been performed and the patient will continue to be receive 
mechanical ventilation PEEP titration via the University of Michigan ARDS 
protocol high PEEP arm. All ventilator management will return to the clinical 
team. 
 

 
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5.1.5 EIT PEEP Titration 
Electrical impedance tomography (EIT) is a non-invasive, non-radioactive, 
bedside imaging tool.  EIT entails the use of a belt like apparatus which is placed 
circumferentially around a patient’s chest.  A small, imperceptible current is 
applied and regional voltages are subsequently measured to determine 
ventilation related impedance changes across the thoracic cross section created 
by the belt.  Reconstruction algorithms are then utilized to generate real time 
tomographic images on a breath by breath basis. The Drager Pulmovista 500, 
which is commercially available in Europe and Canada will be used for the 
generation of EIT images (Appendix D).   
 
In a review of the recent EIT literature, we found 7 studies [18-22] using the 
Drager EIT device in adults to either provide feedback on the effects of PEEP or 
to determine a specific level to set PEEP (see Appendix E).  All 7 studies are 
observational in design, ranging in sample size from 10 to 39 patients.  Five were 
studies of patients with ARDS.  The methods used in most of these studies 
provided a breathing pattern at a modest pressure level (recruitment maneuver) 
to open the maximum number of lung units for that pressure and then gradually 
reduced the end-expiratory pressure (decremental PEEP) to observe the 
patterns of variation in ventilation.   
 
The most common EIT variables used to assess PEEP include: 
1. Regional compliance: it is analogous to dynamic compliance, but rather 
than using a change in tidal volume in the numerator, it uses the tidal 
impedance variation (TIV).  Also, dynamic and static compliance are 
global measurements, while EIT regional compliance reflects the 
compliance in each of the four regions of interest (generally dorsal, 
medial-dorsal, medial-ventral and ventral) 
2. EELI (end-expiratory lung impedance): it is analogous to the end-
expiratory lung volume or functional residual capacity (FRC) 
3. ODCL (overdistension-collapse): this index estimates the percentage and 
location of lung overdistension and atelectasis (collapse) during a 
decremental PEEP trial 
4. GI (global inhomogeneity) index: this quantifies the ventilation distribution 
in the lungs and provides information on the degree of homogeneity of 
lung ventilation 
5. COV (center of ventilation): it reflects the distribution of regional ventilation 
in a dependent-to-non-dependent direction 
 
Patient preparation: 
1. The patient should be sedated adequately to suppress respiratory effort. 
2. The EIT belt will be placed at the level of the 5th intercostal space.  A period of 5-
10 minutes will be allowed for electrode stabilization and calibration. 
 
PEEP Titration Procedure: 
1. The procedure involves two phases: a recruitment phase followed by a gradual 
reduction in the end-expiratory pressure phase (Decremental PEEP). 

 
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2. Recruitment Phase: Pressure control with a drive pressure of 15 cm H2O and 
PEEP of 20 cm H2O (ie, 35/20) will be applied for 5-10 breaths and then 
increased to a PEEP of 25 cm H2O (ie, 40/25) for 1 minute. 
3. Decremental PEEP: In volume control, VT will be set to 6 mL/kg PBW and PEEP 
to 20.  Every 5-10 minutes, PEEP will be reduced by 2 cm H2O.  PEEP will be 
reduced until one of the following occurs: 1) drop in EELI in any region during the 
stabilization period by >10%, 2) PEEP = 5 cm H2O, or 3) patient develops 
hemodynamic instability or SpO2 <88%. 
4. The best EIT-PEEP is identified as that which demonstrates the best 
compromise in over-distension (OD) and collapse (CL), as determine by the 
ODCL EIT variable. 
 
5.1.6 Rescue Procedures 
If PaO2 ≥ 55 mmHg or SpO2 ≥ 88% with FIO2 of 1.0 cannot be maintained or if acidosis 
is severe and cannot be controlled, and alternate therapies (rescue procedures) can be 
employed. Rescue procedures will be chosen according to the University of Michigan 
ARDS protocol (Appendix C), and may include repeated recruitment maneuvers, prone 
positioning, neuromuscular blockade, inhaled nitric oxide, inhaled epoprostenol sodium, 
airway pressure release ventilation, high frequency ventilation, or ECMO.  
 
5.1.7 Other Aspects of Care 
All other aspects of care such as fluids, antibiotics etc. will be determined by the clinical 
team caring for the patient. 
 
6 Data Collection 
6.1 Background Assessments 
1. Demographic and Admission Data (including age, sex, race) 
2. Pertinent Medical History and Physical Examination (including Charlson co-
morbidity score) 
3. Height; gender; measured Body Weight (mBW); calculated predicted body weight 
(PBW); body mass index (BMI) 
4. Time on ventilator prior to enrollment 
5. Risk factors for ARDS (sepsis, aspiration, trauma, pneumonia, drug overdose, 
other) 
6. Ever smoker (>100 cigarettes in lifetime)?   
a. If Yes, current smoker?   
b. If ever smoker, estimate pack years [Pack years = (# packs per day) x 
(number of years smoked)] 
c. If former smoker, when quit? 
 

 
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6.2 Baseline Assessments 
The following information will be recorded during the 24-hour interval preceding 
randomization. If more than one value is available for this 24-hour period, the value 
closest to the time of randomization will be recorded. If no values are available from the 
24 hours prior to randomization, then values will be measured post randomization but 
prior to study initiation.   
 
1. History and physical examination 
2. Vital signs:  heart rate (beats / min), systemic systolic and diastolic BP (mmHg), 
body temperature (0C) 
3. Ventilator mode, rate, minute ventilation, tidal volume, FiO2, PEEP, Pplat, Ppeak, 
and Pmean  
4. Arterial blood gas (PaO2, PaCO2, SaO2, pH) and SpO2  
5. Frontal Chest Radiograph – radiographic lung injury score (# of quadrants) 
6. Administration of the following medications (name) 
(a) Sedatives 
(b) Analgesics 
(c) Vasopressors 
(d) Corticosteroids 
 
7. Presumed site of infection, if sepsis is the etiology of ARDS 
8. APACHE II score, including the acute physiology components 
9. APACHE II demographics plus history of: hypertension, prior myocardial 
infarction, congestive heart failure, peripheral vascular disease, prior stroke 
with sequelae, dementia, chronic pulmonary disease, arthritis, peptic ulcer 
disease 
10. SOFA Score: Cardiovascular, renal, respiratory, hepatic, and hematology organ 
function will be assessed using the SOFA methodology as described in 
Appendix H. 
 
6.3 Assessments During Study 
The following data will provide the basis for assessing protocol compliance and safety 
as well as between-group differences in several efficacy variables. Data for each of the 
variables will be recorded at the times shown in the Time-Events schedule (Appendix 
F).   
 
It is expected that setting PEEP using EIT will take between 20-40 minutes and 5-10 
minutes using the High-PEEP table. To standardize the time from new PEEP exposure 
until inflammatory mediators are obtained, time 0 is defined as the time at which the 
PEEP setting is finally established.  Hour 6 is subsequently six hours after PEEP is 
initially established and the time of the 2nd mini-BAL.  Time 0 resets at the point of 
crossover, as the time at which the new PEEP level is established. (see Appendix F) 

 
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Safety assessment during the mini-BAL 
1. Heart rate, blood pressure and SpO2 will be continuously monitored 
 
Hour 0 of First group (following initial PEEP setting): 
1. Ventilator mode, rate, minute ventilation, tidal volume, FiO2, PEEP, Pplat, Ppeak, 
Pmean, total-PEEP 
2. EIT data 
3. Heart rate, systemic systolic and diastolic BP, SpO2 
 
Hour 1 of First group: 
1. Arterial blood gas (pH, PaCO2, PaO2, SaO2), if collected for standard of care 
2. SpO2 
 
Hour 6 of First group: 
1. Immediately before the mini-BAL 
a. Ventilator mode, rate, minute ventilation, tidal volume, FiO2, PEEP, Pplat, 
Ppeak, Pmean, total-PEEP 
b. EIT data 
c. Heart rate, systemic systolic and diastolic BP, SpO2 
2. Safety assessment during the mini-BAL 
a. Heart rate, blood pressure and SpO2 will be continuously monitored 
3. Immediately following the mini-BAL, the patient will crossover to the other PEEP 
titration method 
 
Hour 0 of Crossover group (following initial PEEP setting): 
1. Ventilator mode, rate, minute ventilation, tidal volume, FiO2, PEEP, Pplat, Ppeak, 
and Pmean, total-PEEP 
2. EIT data 
3. Heart rate, systemic systolic and diastolic BP, SpO2 
 
Hour 1 of Crossover group: 
1. Arterial blood gas (pH, PaCO2, PaO2, SaO2), if collected for standard of care 
2. SpO2 
 
Hour 14 to 18 of Crossover group: 
1. Immediately before the mini-BAL 
a. Ventilator mode, rate, minute ventilation, tidal volume, FiO2, PEEP, Pplat, 
Ppeak, and Pmean, total-PEEP 
b. EIT data 
c. Heart rate, systemic systolic and diastolic BP, SpO2 
2. Safety assessment during the mini-BAL 
a. Heart rate, blood pressure and SpO2 will be continuously monitored 
3. Immediately following the mini-BAL, the patient will be placed on standard 
University study ventilator settings and the study will conclude 
 

 
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16
7 Statistical Considerations  
This study will compare the physiologic and biomarker endpoints from various time 
points:  Usual care first and EIT first groups will be compared with each other at 
baseline and between groups at 6 hours.  The 6-hour crossover point will yield a 
comparison between groups 14-18 hours later, at the completion of the protocol as well 
as a comparison between groups from the 6-hour crossover point.  Quantitative, 
normally distributed variables such as cytokine levels and P/F ratio will be tested via t-
test.  Quantitative, non-normally distributed variables such as driving pressure and 
plateau will be tested via Mann Whitney test.  Categorical variables, such as cause of 
ARDS will be tested via Chi-square. 
 
8 Data Collection  
The research coordinators will collect data and record it either on paper data sheets or 
in a custom-designed computer database. 
 
9 Risk Assessment 
This study involves randomization to usual care or PEEP titration by EIT, and then 
crossover to the other arm. All patients will receive a high PEEP strategy during the 
usual care arm of the protocol.  In addition, mini-BAL will be performed at three time 
points during the protocol on each subject.  
 
9.1 Risks of mini-BAL  
Study subjects will be assessed before, during and for 15 minutes after the mini-BAL.  
Potential complications of the Mini-BAL procedure include pneumothorax, bronchial 
hemorrhage, vagal reflex, bronchial irritation, and transient arterial hypoxemia.  Prior to 
performing mini-BAL the study subject’s FiO2 will be increased to 1.0 ten (10) minutes 
prior to the start of the procedure.  Mini-BAL will not be performed if the P/F ratio is < 
100 or the imputed S/F ratio is less than 89.  Mini-BAL will not be performed if the 
platelet count < 50 K/uL.  During performance of the mini-BAL the procedure will be 
terminated for a saturation <89% sustained for greater than 1 minute following the 
administration of any aliquot.  The early termination of the mini-BAL, based on the 
above criteria, will be reported as an adverse event.  
 
9.2 Risks of High PEEP 
Historical risks include pneumothorax and hypotension. However, no significant 
differences in pneumothorax or barotrauma, nor vasopressor use or circulatory and 
other organ failures were noted in randomized trials save for the ART trial, which used a 
decremental PEEP approach following an aggressive high pressure, long duration 
recruitment maneuver.  This was felt to be largely accountable to the aggressive 
recruitment maneuver, which will not be used as part of this protocol.[25] Recruitment 
maneuvers in both groups (if required in the High-PEEP group during routine 
management) will be performed in accordance with University of Michigan protocol 

 
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(Appendix I).  High-PEEP management will also follow our standard University of 
Michigan guidelines for clinical practice. 
 
9.3 Risk of Death 
It is unlikely that one treatment arm may lead to more deaths; mortality will be monitored 
during the course of the 24-hour study, but is not a clinical outcome of this trial. 
 
9.4 Minimization of Risks 
Federal regulations at 45 CFR 46.111(a)(1) require that risks to subjects are minimized 
by using procedures which are consistent with sound research design. Oxygen 
saturations and arterial blood gases, if indicated, will be monitored during the mini-BAL 
procedures.  We will use a high PEEP protocol based on those used in multiple large 
clinical trials, that were shown safe, feasible, and of potential clinical benefit for the 
intended population or moderate to severe ARDS. The DSMB will be reviewing data as 
outlined above and will examine not only efficacy but safety (inclusive of mortality) and 
will reserve the right to halt the study at any time.  
 
9.5 Potential Benefits 
Study subjects may or may not receive any direct benefits from their participation in this 
study. High PEEP has been shown to improve oxygenation in ARDS, to be safe in 
multiple large trials, and of potential benefit in moderate-severe ARDS. This approach is 
routinely chosen by most clinicians.  Titration of PEEP by EIT, if anything, should be 
safer than using the customary PEEP table insofar as it provides real time insight into 
whether lung zones are being over ventilated and manifesting tidal hyperinflation. 
 
9.6 Risks in Relation to Anticipated Benefits 
Federal regulations at 45 CFR 46. 111 (a)(2) require that “the risks to subjects are 
reasonable in relation to anticipated benefits, if any, to subjects, and the importance of 
the knowledge that may reasonably be expected to result.”  Based on the preceding 
assessment of risks and potential benefits, the risks to subjects are reasonable in 
relation to anticipated benefits.   
 
Procedures – Mini-BAL can result in transient worsening of hypoxemia. This is usually 
transient in nature. Mini-BAL will not be performed for a P/F ratio <100 or an S/F ratio 
<89 and will be terminated for a S/F ratio of <89 for more than one minute.  Mini-BAL 
can result in lung irritation and bleeding.  Mini-BAL will not be performed if platelets < 50 
K/uL. 
 
Treatments – High PEEP is routinely used in clinical practice. The EIT belt is 
noninvasive and minimally discomforting to wear. There is potential for benefit to society 
and individual patients should EIT prove to be result in less lung inflammation and a 
large clinical trial were to demonstrate clinical benefit. 
 

 
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18
10 Human Subjects 
Each study participant or a legally authorized representative must sign and date an 
informed consent form. Institutional review board approval will be required before any 
subject is entered into the study.  
 
10.1 Selection of Subjects 
10.1.1 Equitable Selection of Subjects  
Federal regulations at 45 CFR 46(a)(3) require the equitable selection of subjects. The 
Emergency department and Critical Care Medicine Unit will be screened to determine if 
any patient meets inclusion and exclusion criteria. Data that have been collected as part 
of the routine management of the subject will be reviewed to determine eligibility. No 
protocol-specific tests nor procedures will be performed as part of the screening 
process. If any subjects meet criteria for study enrollment, then the attending physician 
will be asked for permission to approach the patient or his/her LAR for informed 
consent. Study exclusion criteria neither unjustly exclude classes of individuals from 
participation in the research nor unjustly include classes of individuals from participation 
in the research. Hence, the recruitment of subjects conforms to the principle of 
distributive justice.  
 
10.1.2 Justification of Including Vulnerable Subjects  
The present research aims to investigate the safety and efficacy of a type of treatment 
for patients with ARDS.  Due to the nature of ARDS and its risk factors (e.g., sepsis, 
trauma), the vast majority of these patients will have impaired decision-making 
capabilities. This study cannot be conducted if limited to enrolling only those subjects 
with retained decision-making capacity. Hence, subjects recruited for this trial are not 
being unfairly burdened with involvement in this research simply because they are 
easily available. 
 
10.2 Informed Consent 
Federal regulations 45 CFR 46.111(a)(5) require that informed consent will be sought 
from each prospective subject or the subject’s legally authorized representative (LAR). 
As we will enroll critically ill, intubated patients, we anticipate almost all consents will be 
from the subject’s LAR, and thus the remainder of this section will focus on LARs. The 
investigator is responsible for ensuring that the LAR understands the risks and benefits 
of participating in the study, and answering any questions the LAR may have throughout 
the study and sharing any new information in a timely manner that may be relevant to 
the LAR’s willingness to continue the subject’s participation in the trial. The consenter 
will make every effort to minimize coercion. All study participants or their LARs will be 
informed of the objectives of the study and the potential risks. The informed consent 
document will be used to explain the risks and benefits of study participation to the LAR 
in simple terms before the patient is entered into the study, and to document that the 
LAR is satisfied with his or her understanding of the risks and benefits of participating in 
the study and desires to participate in the study.  The investigator is responsible for 
ensuring that informed consent is given by each LAR. This includes obtaining the 

 
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19
appropriate signatures and dates on the informed consent document prior to the 
performance of any protocol procedures. 
 
10.3 Withdrawal of Consent 
Patients may withdraw or be withdrawn (by the patient or LAR) from the trial at any time 
without prejudice. Data recorded up to the point of withdrawal will be included in the trial 
analysis, unless consent to use their data has also been withdrawn.   
 
10.4 Identification of Legally Authorized Representatives 
Many of the patients approached for participation in this research protocol will invariably 
have limitations of decision-making abilities due to their critical illness. Hence, most 
patients will not be able to provide informed consent.  Accordingly, informed consent will 
be sought from the potential subject’s legally authorized representative.   
 
Regarding proxy consent, the existing federal research regulations (‘the Common Rule’) 
states at 45 CFR 46.116 that “no investigator may involve a human being as a subject 
in research…unless the investigator has obtained the legally effective informed consent 
of the subject or the subject’s legally authorized representative”; and defines at 45 CFR 
46 102 (c) a legally authorized representative (LAR) as “an individual or judicial or other 
body authorized under applicable law to consent on behalf of a prospective subject to 
the subject’s participation in the procedures(s) involved in the research.” OHRP defined 
examples of “applicable law” as being state statutes, regulations, case law, or formal 
opinion of a State Attorney General that addresses the issue of surrogate consent to 
medical procedures. Such “applicable law” could then be considered as empowering the 
LAR to provide consent for subject participation in the research.  
 
According to a previous President’s Bioethics Committee (National Bioethics Advisory 
Committee), an investigator should accept as an LAR…a relative or friend of the 
potential subject who is recognized as an LAR for purposes of clinical decision making 
under the law of the state where the research takes place (National Bioethics Advisory 
Commitee (NBAC), 1998). Finally, OHRP has opined in their determination letters that a 
surrogate could serve as a LAR for research decision making if such an individual is 
authorized under applicable state law to provide consent for the “procedures” involved 
in the research study (Office of Human Research Protections (OHRP), 2002).      
 
10.5 Justification of Surrogate Consent 
According to the Belmont Report, respect for persons incorporates at least two ethical 
convictions; first, that individuals should be treated as autonomous agents, and second, 
that person with diminished autonomy are entitled to protection. One method that 
serves to protect subjects is restrictions on the participation of subjects in research that 
presents greater than minimal risks. Commentators and Research Ethics Commissions 
have held the view that it is permissible to include incapable subjects in greater than 
minimal risk research as long as there is the potential for beneficial effects and that the 
research presents a balance of risks and expected direct benefits similar to that 
available in the clinical setting (Dresser, 1999). Several U.S. task forces have deemed it 
is permissible to include incapable subjects in research. For example, the American 

 
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College of Physicians’ document allows surrogates to consent to research involving 
incapable subjects only “if the net additional risks of participation are not substantially 
greater than the risks of standard treatment.” (American College of Physicians, 1989). 
Finally, the National Bioethics Advisory Committee (NBAC) stated that an IRB may 
approve a protocol that presents greater than minimal risk but offers the prospect of 
direct medical benefits to the subject, provided that…the potential subject’s LAR gives 
permission…” (National Bioethics Advisory Committee (NBAC), 1998) 
 
Consistent with the above ethical sensibilities regarding the participation of decisionally 
incapable subjects in research and the previous assessment of risks and benefits in the 
previous section, the present trial presents a balance of risks and potential direct 
benefits that is similar to that available in the clinical setting, with the exception of the 
additional blood draws.     
 
10.6 Additional Safeguards for Vulnerable Subjects   
The present research will involve subjects who might be vulnerable to coercion or 
undue influence. As required in 45CFR46.111(b), we recommend that additional 
safeguards be included to protect the rights and welfare of these subjects. Such 
safeguards might include, but are not limited to: a) assessment of the potential subject’s 
capacity to provide informed consent, b) requirement for subject’s assent, c) the 
availability of the LAR to monitor the subject’s subsequent participation and withdrawal 
from the study; d) augmented consent processes.  
 
10.7 Confidentiality 
Federal regulations at 45 CFR 46 111 (a) (7) requires that when appropriate, there are 
adequate provisions to protect the privacy of subjects and to maintain the confidentiality 
of data. To maintain confidentiality, study related data and reports will identify subjects 
by a coded number only. Only the study research teams will have access to the codes. 
All records will be kept in a secure password protected computer.  All computer entry 
and networking programs will be done with coded numbers only. All paper case report 
forms will be maintained in a locked cabinet inside a locked office. Clinical information 
will not be released without the written permission of the patient. 
 
11 Adverse Events  
Assuring patient safety is an essential component of this protocol. Each participating 
investigator has primary responsibility for the safety of the individual participants under 
his or her care. The Investigators will determine daily if any clinical adverse experiences 
occur during the period from enrollment through the end of the protocol, 24 hours after 
enrollment.   
 
The following adverse events will be collected in the adverse event case report forms: 
• Serious adverse events 
• Non-serious adverse events that are considered by the investigator to be 
related to study procedures 

 
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• Adverse events that lead to permanent discontinuation of the study 
procedures 
A clinical trial adverse event is any untoward medical event associated with the use of a 
drug or study procedure in humans, whether or not it is considered related to a drug or 
study procedure.   
 
If a patient's treatment is discontinued as a result of an adverse event, study site 
personnel must report the circumstances and data leading to discontinuation of 
treatment in the adverse event case report forms.   
 
Clinical Outcomes 
Routine clinical outcomes of ARDS are exempt from adverse event reporting unless the 
investigator deems the event to be related to the conduct of study procedures. The 
following are examples of events that will be considered clinical outcomes: 
• Death related to ARDS or a sequela of ARDS based on the interpretation 
of the investigator. 
• Cardiovascular events: the need for vasoactive drugs or fluids for 
hypotension or hypotension. 
• Respiratory events: decreased PaO2/FiO2, hypoxia, worsening acute 
respiratory distress syndrome, or respiratory failure, unless related to 
performance of the mini-BALs. 
• Hepatic events: hepatic injury or liver dysfunction that leads to an increase 
from baseline in the serum level of bilirubin.  
• Renal events: renal failure, renal insufficiency, or renal injury that leads to 
an increase from baseline in serum creatinine. 
• Hematologic/coagulation events: coagulopathy, disseminated 
intravascular coagulation, thrombocytopenia, or thrombocytosis. 
• Systemic inflammatory response syndrome related criteria: tachypnea, 
tachypnea, leukocytosis, leukopenia, hypothermia, hyperthermia, 
tachycardia, or bradycardia that does not meet the definition of severe and 
prolonged. 
Note: Arrhythmias such as atrial fibrillation, heart block, ventricular tachycardia or 
ventricular fibrillation are not considered clinical outcomes and should be recorded as 
adverse events if they are serious events, are considered by the investigator to be 
related to study protocol, or lead to discontinuation of the protocol. 
 
Serious Adverse Events 
Serious adverse event collection begins after the patient or surrogate has signed 
informed consent.  If a patient experiences a serious adverse event after consent, but 
prior to protocol initiation, the event will NOT be collected unless the investigator feels 
the event may have been caused by a protocol procedure. 
 

 
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Study site personnel must alert the principal investigator or his designee of any serious 
and study procedure related adverse event within 24 hours of investigator awareness 
of the event.   
 
A serious adverse event is any adverse event that results in one of the following 
outcomes and is not classified as a clinical outcome of ARDS using the definitions noted 
above: 
• Death that is not related to ARDS or a sequela of ARDS or death that is 
considered by the investigator to be related to study procedures 
• A life-threatening experience (that is, immediate risk of dying) 
• Persistent or significant disability/incapacity 
Important medical events that may not result in death or be life-threatening may be 
considered serious adverse events when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention. 
 
Data Safety Monitoring Board 
This study will use a DSMB to regularly monitor data from this trial, review and assess 
the performance of its operations, and make recommendations.  Three members of the 
Division of Pulmonary and Critical Care Medicine, Division of Acute Care Surgery 
and/or Division of Emergency Critical Care who are not involved in this project will 
independently review this study on a semi-annual basis. 
 
 

 
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APPENDICES 
A. Exclusion Definitions 
1. Child-Pugh Score (Pugh, 1973) 
 
Points  
Class 
 
   5-6               A 
 
   7-9  
   B 
 
 
  ≥ 10  
   C 
 
 
 
 
 
 
  
Numerical Score for Increasing 
Abnormality 
Measurement 
1 
2 
3 
Ascites 
None 
Present 
Tense 
Encephalopathy 
None 
Grade I or II 
Grade III or IV 
Bilirubin (mg/dl) 
< 2 
2-3 
> 3 
Albumin (g/L) 
> 35 
28-35 
< 28 
Prothrombin time (sec. prolonged) 
1-4 
4-10 
> 10 
 
 
2. Severe Chronic Respiratory Disease 
Any of the following is considered severe chronic respiratory disease and excludes 
a patient from being eligible for enrollment: 
a. 
FEV1 less than 20 ml/kg PBW (e.g. 1.4 L for a 70 kg person), or  
b. 
FEV1/VC less than 50% predicted, or  
c. 
Chronic hypercapnia (PaCO2 greater than 45 mmHg) and/or chronic 
hypoxemia (PaO2 less than 55 mmHg) on FIO2 = 0.21, or  
d. 
Radiographic x-ray evidence of any chronic over-inflation or chronic 
interstitial infiltration, or  
e. 
Hospitalization within the past six months for respiratory failure in patients 
with chronic respiratory disease.  (PaCO2 greater than 50 mmHg or PaO2 
less than 55 mmHg or O2-Sat < 88% on FiO2 = .21).  
f. 
Chronic restrictive, obstructive, neuromuscular, chest wall or pulmonary 
vascular disease resulting in severe exercise restriction, e.g., unable to climb 
stairs or perform household duties, secondary polycythemia, severe 
pulmonary hypertension (mean PAP greater than 40 mmHg), or ventilator 
dependency. 
 
 
 

 
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B. Flowchart of Management of EIT Study Groups 
 
 
 
 
 
 
Receiving MV on 
UM Settings
Randomized
Confirm on PEEP/
FiO2 table and other 
ARDSNet guidelines
BAL
Manage per 
ARDSNet guidelines, 
using High-PEEP 
table
6 hr 
since initial
BAL?
Manage per 
ARDSNet guidelines, 
using EIT-PEEP
14-18 hr on 
protocol?
BAL
BAL
Standard Care 
First Group 
(High-PEEP table)
EIT-PEEP
First Group 
Confirm on  
ARDSNet guidelines
BAL
 Manage per 
ARDSNet guidelines, 
using EIT-PEEP
6 hr 
since start EIT-
PEEP?
BAL
Manage per 
ARDSNet guidelines, 
using High-PEEP 
table
14-18 hr on 
protocol?
BAL
Study Complete
Study Complete
Determine EIT-PEEP
Determine EIT-PEEP
Crossover to 
Standard Care 
group for 14-
18 hours
Go to #2
From Standard 
care Cross-
over
From EIT-PEEP 
Cross-over
Crossover to 
EIT-PEEP group 
for 14-18 
hours
Go to #1
2
1
Yes
Yes
No
No
Yes
No
Yes
No

 
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C. ARDS Ventilator Management Strategies 
 

 
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26
 
 

 
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27
  

 
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28
 
E. EIT Studies 
 
  
Adult Studies using Dräger Pulmovista EIT to assess PEEP
(as of 7/31/18)
Author, 
Year
Design
Patients
EIT best PEEP
Other PEEP  
method(s)
Protocol
EIT Measures
Outcome
Heines,
2018
Observ-
ational; 
describe 
clinical 
practice
ARDS
(n=39)
Best compromise 
in OD vs CL 
(Costa)
Physician 
preference
 - PCV constant IP; 
 - (RM) Incremental PEEP (to 18-20)
 - Decremental PEEP by 2 cmH2O steps; stop when 
loss in EELI (derecruitment), RM, decr until EELI 
loss in dependent area
 -  Do offline analysis
EELI, offline analysis: 
ODCL-like, 
 -  EIT acquisition feasible in all pts; no complications with trials,
 -  set vs EIT PEEP same (11.7 vs 11.3), but variable individual 
agreement
 -  28% of pts was a diff by >4 cm (cln relevant), 38% same
 -  after set to EIT PEEP increased C and P/F (in both <4 and those >4, 
so RM?)
Karsten, 
2017
Observ-
ational
Mild to 
Moderate 
ARDS
(n=15)
Used both ODCL 
and COV index 
(i.e., 2 Best EIT)
Cdyn (lowest 
PEEP 
associated with 
highest C)
 - VC w/ 7 ml/kg IBW
 - (RM) Incremental PEEP, starting at 0 to 15 in 5 
mbar steps Q4 min, if PIP=40 not reached PEEP 
increased to 20 and 25. 
 - Decremental PEEP in 2 mbar steps from 15 to 5 
Q4 min.
ODCL, COV index
 - Best PEEP by COV resulted in lower PEEP than Best PEEP 
compliance, 
 - Best PEEP per ODCL was higher than based on compliance.
 - The best compliance did not correspond to PEEP with least 
overdistension and collapse.
(Mean PEEP: BestPEEPCOV < BestPEEPcompl <BestPEEPODCL)
Franchineau, 
2017
Observ-
ational
Severe 
ARDS on 
ECMO
(n=15)
Best compromise 
betw CL and OD; 
CL of <15% with 
lowest % OD
N/A
 - PC w/ delta-P=14, PEEP 20 (34/20) x20 min
 - Decremental PEEP from 20 to 0 (if tol), by 5 Q20 
min; (no RM pretrial) 
ODCL; EELI, delta-
impedance
 - EIT PEEP was 15, 10 and 5, in 7, 6 and 2 pts respectively; 20 and 0 
never selected
 - High PEEP associated with more OD (50% in some) and lower CL 
lower PEEP associated with CL (>70% in some) 
 - Wide variability of CL and OD among the 5 PEEP levels suggests 
need for EIT
 - tidal vol distribution w/decr PEEP trial decreases in medial-dorsal and 
dorsal and increases in medial ventral and ventral
Eronia, 
2017
Observ-
ational
ARDS 
(N=16)
delta EELI 
(variation)
Lower PEEP 
table
 - Baseline x 20 min: ARDSNet protocol (VC, 6, <30, 
lower PEEP table, f to pH7.3-7.45, etc.)
 - RM 40x40, if Delta EELI change >10%, RM 40x40, 
increase PEEP 2 measure delta EELI again (max 
PEEP=18)
 - Also measurements at EIT-PEEP +2
 - Regional compliance 
(Vt%/100*compliance), 
 - Alveolar 
hyperdistension and 
collapse,  
 - Amount of recruited 
volume
 - 14 of 16 could get good data; mean 48 min to complete study
 - EIT-PEEP higher than table-PEEP (13 vs 9)
 - P/F increased and drive-pressure reduced with EIT-PEEP
 - calculated that EXPRESS PEEP would be 20.6 vs EIT_PEEP (13.1)
 - Regional alv OD and CL reduced in dependent and increased in non-
dependent
Long, 2015
Observ-
ational
ARDS 
(n=18)
Level to prevent 
sign CL w/o 
obvious OD
Baseline 
PEEP/FiO2 
method not 
specific, just to 
SpO2 >90%
 - Baseline (VC w/6 mL/kg (5 or 4 for Pplat), 
Pplat<30, PEEP/FiO2 for SpO2 >90%) x10-15 min
 - ZEEP: PEEP=0, FiO2=1.0, x3-5 min
 - RM: PEEP to 15 x2 min, if Pplat<40, to 20 x2 min
 - Decremental: 20 to 5 by 3 Q5-10 min
 - 2 groups based on RM PaO2+PaCO2 on 100%: 
Responders(R) >400 vs Non-responders (NR) <400
 - % recruited pixels
 - % OD pixels
 - GI-TV and GI-FRC
 - 18 pts, 10 male, 12 w/pneumonia, 
 - 13 responders (pneumonia in 35 (R) vs 80% (NR), p=0.062)
 - No diff in ZEEP P/F; PEEP-15: P/F 302 vs 104; PEEP-20: 369 vs 121
 - In R: PEEP mainly increased recruitment in dependent and OD in 
nondependent. PEEP alleviated global inhomogeneity of VT and EELV.  
 - PEEP levels w/o significant CL and OD were identified individually
Blankman, 
2014
Observ-
ational
Post 
cardiac 
surgery
(n=12)
PEEP with 
minimal lung 
collapse & 
minimal OD
 - Cdyn
 - P/F
 - Ventilated on PC with constant delta-P, I:E, f, FiO2 
throughout study
 - RM: delta-P=20 while PEEP increased from 5 to 
20, by 5 so that 40/20, held for 40 sec
 - Decremental: delta-P=10 and PEEP=15 x15 min, 
then drop by 5 to 0 Q10-20 min
 - TIV
 - VSA
 - COV
 - GI index
 - Regional compliance
 - ITV index (new)
 - Cdyn and P/F had highest value at 10 and 15 PEEP
 - Max values for TIV, regional C and VSA in nonresponders was 5, in 
responders was 15
 - GI index lowest at 10, while COV and RVD index was 15 PEEP
 - Concluded ITV index was comparable to Cdyn to indicate "best 
PEEP"
Zhao, 
2010
Observ-
ational
Periop
(n=10)
Lowest GI index
 - Cdyn (least 
sq.); 
 - Intra-tidal 
compliance-
volume curve
 - VC (10 mL/kg), f-12, 1:1.5, 100%
 - Incremental PEEP, 0 to 28 by 2, each for 10 
breaths
GI index
 - PEEP values for 3 methods: EIT-GI: 12.2; Cdyn:11.4; compliance-
volume: 12.2
 - Feasible and reasonable to use GI index to select PEEP with respect 
to ventilation homogeneity

 
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F. Time-Event Schedule 
 
 
 
 
 
Clock
example
Study
hour
Procedures
Vent 
data
EIT 
data
HR/
BP
SpO2 ABG Cytokines
Comments
closest
BL, pre
BL Assess
X
X
X
X
8:00
BAL#1
X
X
X
BAL procedure time ~30 min
8:30
0
Set PEEP #1
X
X
X
X
Set EIT ~20-40 min vs table ~5-10 min
9:30
1
X
X
ABG 1 H after setting PEEP
10:30
2
11:30
3
12:30
4
13:30
5
pre BAL
Assessment
X
X
X
X
X
14:30
6
BAL #2
X
X
X
BAL procedure time ~30 min
15:00
0
Set PEEP #2
X
X
X
X
16:00
1
X
X
ABG 1 H after setting PEEP
17:00
2
18:00
3
19:00
4
20:00
5
21:00
6
22:00
7
23:00
8
0:00
9
1:00
10
2:00
11
3:00
12
4:00
13
5:00
14
BAL #3, anytime between hr 14-18
6:00
15
7:00
16
8:00
17
9:00
pre-BAL
Assessment
X
X
X
X
X
9:00
18
BAL #3
X
X
X
BAL procedure time ~30 min
Data Collected: Ventilator:
mode, set VT, RRset, RRtot, VE, FiO2, PEEP, Ppeak, Pplat, Pmean, PEEPtot, 
vent calcs:
drive-P, Cst, Cdyn, 
EIT:
delta-EELI, ODCL; COV, GI Index, Regional compliance
ABG:
pH, PaCO2, PaO2, SaO2, BE, HCO3 (if collected for standard of care)
Cytokines:
per protocol
Definition of Time: Time 0 is when PEEP is extablished
Time 6 is 6 hours after PEEP is set
Reset time frames at cross-over

 
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G. Imputed PaO2/FiO2 
 
 
 
The table is used when an ABG is not available to calculate the PaO2/FiO2.  Instead, the 
SpO2 and FiO2 are used to impute what the PaO2/FiO2 might be.  The following 
conditions must be met:  
1. SpO2 between 80-96% 
2. SpO2 should be measured at least 10 minutes after any FiO2 change 
3. PEEP must be >8 cm H2O 
4. An adequate pulse oximetry waveform tracing is present 
 
 

 
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31
H. SOFA Scoring System 
SOFA Score 
0 
1 
2 
3 
4 
RespirationA 
PaO2/FiO2 (mmHg) or 
imputed P/F using 
SaO2/FiO2 
>400 
<400 
<300 
<200 
<100 
Coagulation 
Platelets 103/mm3 
>150 
<150 
<100 
<50 
<20 
Liver 
Bilirubin (mg/dL) 
<1.2 
1.2-1.9 
2.0-5.9 
6.0-11.9 
>12.0 
CardiovascularB 
Hypotension 
No 
hypotension 
MAP<70 
Dopamine 
</= 5 or 
dobutamine 
(any) 
Dopamine >5 
or 
norepineprine 
</= 0.1 
Dopamine >15 
or 
norepinephrine 
>0.1 
Renal 
Creatinine (mg/dL) or 
urine output (mL/d) 
<1.2 
1.2-1.9 
2.0-3.4 
3.5-4.9 or 
<500 
>5.0 or  
<200 
A:  Values for scores 3 and 4 are with respiratory support 
B:  Adrenergic agents administered for at least one hour (doses given in mcg/kg/min) 
 
 

 
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I. Recruitment Maneuver Policy (on file) 
 
 
 
 
 

 
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