EIT- Guided Lung Recruitment in Pediatric Acute Respiratory Distress Syndrome
Phase: NA
Conditions: Acute Respiratory Distress Syndrome
Sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

 
 
 
 
 
Dipartimento di Anestesia, Rianimazione ed Emergenza-Urgenza 
UOC Anestesia e Terapia Intensiva Donna Bambino 
        - 
Direttore: E. Calderini 
Responsabile: Dott.ssa Giovanna Chidini 
mail: giovanna.chidini@policlinico.mi.it 
 
 
 
 
 
 
 
 
REcruitment MAneuvers and Mechanical Ventilation guided by EIT in pediatric Acute Respiratory 
Distress Syndrome (pARDS) 
 
Acronym:  
REMAV-EIT  
 
Unique ID Protocol  1170_2021 
 
Version and date: Version 1.0 – Date 11.11.2021.  
 
 
 
 
 
 
 
 
 
 
 

 
 
 
REcruitment MAneuvers and Mechanical Ventilation guided by EIT in pediatric Acute Respiratory 
Distress Syndrome (pARDS) 
 
Acronym:  
REMAV-EIT  
 
 
Version and date: Version 1.0 – Date 11.11.2021.  
 
Document: Study protocol 
 
Promoter: Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Sforza28, 20122 Milano, 
Italy 
 
Study site: U.O.C. Anestesia e Terapia Intensiva Donna-Bambino, Fondazione IRCCS Ca’ Granda 
Ospedale Maggiore Policlinico, Via Sforza 35, 20122 Milano, Italia 
 
Principal Investigator: Dr.ssa Giovanna Chidini 
U.O.C. Anestesia e Terapia Intensiva Donna-Bambino, Fondazione IRCCS Ca’ Granda Ospedale 
Maggiore Policlinico, Via Sforza 35, 20122 Milano, Italia 
 
Confidential Statement 
The information contained in this document, especially unpublished data, is the property of 
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and is therefore provided to you in 
confidence. It is understood that this information will not be discussed to others without written 
authorization from Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico. 
 

 
 
 
LIST OF ABBREVIATIONS 
ALI = Acute Lung Injury 
ANOVA = ANalysis Of VAriance 
CI = Confidential Interval 
CCW= Chest Wall Compliance 
Crs= Compliance Respiratory System 
Cl=  Compliance Lung  
cmH2O = centimetres of water 
DP= Driving Pressure 
EC = Ethics Committee 
ECG = Electrocardiogram 
EIT = Electrical Impedance Tomography 
FiO2 = Fraction of inspired Oxygen 
GC = Geometric Centre 
GI = Global Inhomogeneity Index 
HR = Heart Rate 
IC = Informed Consent 
ICU = Intensive Care Unit 
LIP= Lower Inflection Point 
mmHg = millimetres of mercury 
NIBP = Non-Invasive Blood Pressure 
pARDS=pediatric Acute Respiratory Distress Syndrome 
PEEP = Positive End Expiratory Pressure 
PIM2= Pediatric Index of Mortality 
PELOD= Paediatric Logistic Organ Dysfunction score  
Plung= Transpulmonary pressure 
ROI = Region Of Interest 
RVD = Regional Ventilation Delay 

 
 
 
SpO2 = peripheral oxygen saturation 
SRM = Stepwise Recruitment Maneuver 
TID = Tidal Impedance Distribution 
CE: Ethical Committee 
CI: informed Consent 
CRF: Case Report Form 
GCP: Good Clinical Practice  
 
 

 
 
 
INDEX 
1. INTRODUCTION ................................................................................................................................ 7 
1.1 Background and rational ............................................................................................................ 7 
2. AIM/S OR HYPOTHESIS OF THE STUDY ............................................................................................ 8 
3. STUDY DESIGN .................................................................................................................................. 9 
3.1 Study design ............................................................................................................................... 9 
3.2 Inclusion criteria ......................................................................................................................... 9 
3.3 Exclusion criteria ........................................................................................................................ 9 
4. STUDY PROCEDURES ...................................................................................................................... 10 
4.1 Standard of Care Treatment in pARDS ..................................................................................... 10 
4.2 Intervention of the Study ................................................................ Error! Bookmark not defined. 
5. ENDPOINT ...................................................................................................................................... 16 
5.1 Primary endpoint ...................................................................................................................... 16 
5.2 Secondary endpoint ................................................................................................................. 16 
6. DURATION/STUDY TIMELINE ......................................................................................................... 16 
7. STATISTICAL ANALYSIS ................................................................................................................... 16 
7.1 Sample size calculation and statistical analysis ........................................................................ 17 
7.2 Data analysis ............................................................................................................................. 17 
8. ADVERSE EVENTS / DEVICE DEFICIENCIES ..................................................................................... 17 
9. RISKS AND BENEFIT EVALUATION .................................................................................................. 17 
10. STUDY MANAGEMENT ................................................................................................................. 18 

 
 
 
10.1 Collection and management of data ...................................................................................... 18 
10.2 Regulatory aspects and ethical considerations ...................................................................... 19 
10.2.1 Approval of the Competent Authority ............................................................................ 19 
10.2.2 Approval of the Ethics Committee .................................................................................. 19 
10.2.3 Informed consent (IC) ...................................................................................................... 19 
10.3 Duties of the experimenter .................................................................................................... 20 
10.4 Study monitoring .................................................................................................................... 20 
10.5 Quality assurance of the study ............................................................................................... 21 
10.6 Study closure .......................................................................................................................... 21 
10.7 Archiving of documents ......................................................................................................... 22 
10.8 Disclosure of information concerning scientific discovery .................................................... 22 
10.8.1 Confidentiality ................................................................................................................. 22 
10.8.2 Publications...................................................................................................................... 22 
11. ALLOWANCES AND COMPENSATION FOR DAMAGE ................................................................... 22 
12. PROTOCOL AMENDMENTS .......................................................................................................... 22 
13. FINANCIAL AGREEMENTS ............................................................................................................. 23 
14. DISCLOSURES ON CONFLICTS OF INTEREST ................................................................................. 23 
15. REFERENCES ................................................................................................................................. 24 
 
 

 
 
 
1. INTRODUCTION 
1.1 Background and rational 
There is evidence from randomized controlled trials in adult patients with Acute Respiratory Distress 
Syndrome (ARDS) suggesting that delivering small tidal volumes with adequate levels of Positive 
End-Expiratory Pressure (PEEP) and a restrictive fluid strategy could improve outcome (1–3). 
However, there is also evidence that there is a dichotomy in outcome in patients with ARDS and not 
all patients respond uniformly (4–8). Concurrent with these data and with the common bedside 
experience that individual patients may or may not respond to interventions, such as escalation of 
PEEP or positional changes, there may be a role for a more personalized ventilator strategy. This 
strategy could account for the unique individual morphology of lung disease, such as the amount of 
atelectasis and overdistension as a percentage of total lung tissue, the exact location of atelectasis, 
and whether positional changes or elevation of PEEP produce lung recruitment or overdistension.  
Recruitment is the dynamic process of opening previously collapsed lung units by increasing 
transpulmonary pressure. Lung units can be kept open by airway pressures that are lower than those 
required to open them, leading to the concept of recruitment using periodic higher pressure 
maneuvers with application of PEEP to maintain alveolar patency.  Stepwise Recruitment maneuvers 
(SRMs) in pARDS improve oxygenation in majority of patients. SRMs should be considered for use 
on an individualized basis in patients with pARDS should be considered if SpO2 decreases by ≥ 5% 
within 5 minutes of disconnection during suction or coughing or agitation.  If a recruitment 
maneuver is conducted, a decremental PEEP trial must be done to determine the minimum PEEP 
that sustains the benefits of the recruitment maneuver.  
 
Electrical impedance tomography (EIT), a bedside monitor to describe regional lung volume changes, 
displays a real-time cross-sectional image of the lung. Regional volume changes during EIT have 
been highly correlated with volume changes detected on bedside. EIT is a non-invasive, non-

 
 
 
operator dependent, bedside, radiations-free diagnostic tool, feasible in paediatric patients and 
repeatable. It allows to study ventilation distribution dividing lungs in four Region Of Interest (ROI). 
The increase in chest impedance is related to the increased presence of air. Therefore, for each 
respiratory act, EIT attributes the value of 100% of the current tidal volume to the overall impedance 
change of the entire chest. Then, it attributes a percentage of the global lung volume to each of the 
ROI, based on regional impedance changes, thus showing how ventilation is distributed in the areas 
concerned. ROI can be defined by quadrants or layers distributed in an anteroposterior direction. 
For the aim of our study, we are going to divide lungs in four dorsoventral ROIs. In addition, EIT 
measures and calculates other parameters that are related not only to the distribution of ventilation, 
but also to the homogeneity of ventilation and the response to certain therapeutic maneuvers, such 
as SRMs or PEEP-application (12-16). The aim of this study is to provide a protocolized  strategy to 
assess optimal recruitment and PEEP setting, tailored on the patients individual response in  
paediatric Acute Respiratory Distress Syndrome (pARDS).   
 
2. AIM/S OR HYPOTHESIS OF THE STUDY 
The primary aim of the study is to assess the Global Index (GI) (as an index of atelectrauma, supra-
distention and in general an inhomogeneous ventilation) measured  after EIT-guided mechanical 
ventilation (Staircase Recruitment Maneuver followed by a decremental PEEP trial with the final 
PEEP value set according with EIT bedside monitoring), compared to the baseline GI value registered 
during mechanical ventilation set  by the physician according to clinical protocolized criteria.  
The secondary aim of the study is to describe the followings parameters: differences in Tidal 
Impedance Distribution, Gravity Centre (GC), Respiratory Mechanics, Blood gases level and 
physiological parameters (respiratory rate, heart rate, systolic and diastolic blood pressure). 
 
3. STUDY DESIGN 

 
 
 
3.1 Study design 
Monocentric, non pharmacologic prospective interventional trial  
Recruitment method: selective invitation 
Eligible patients will be enrolled in the first 48 hours from intubation (17).  
3.2 Inclusion criteria 
- 
Intubated and mechanically ventilated children, ageing 1 months-10 years and meeting the 
PALICC definition for pediatric Acute Respiratory Distress Syndrome (pARDS) (Figure 1.)  
- 
Informed Consent signed 
3.3 Exclusion criteria 
Patients with one or more of the following characteristics will be excluded: 
• Previous barotrauma (pneumothorax, pneumomediastinum or subcutaneous emphysema) 
• Signs of intracranial hypertension  
• Cyanotic congenital cardiac disease 
• Dorso-lumbar pathologies or other bone pathologies associated with restrictive lung 
disease (such as scoliosis, kyphosis) 
• Implantable devices not compatible with EIT (such as pace-makers and implantable 
cardioverter defibrillator) 
• Controindication to positioning the esophageal catheter (surgery, esophageal stenosis) 
4. STUDY PROCEDURES 
The process for obtaining the informed consent must comply with the regulatory procedures in 
force. The investigator (or a designated collaborator) and the subject must date and sign the 
informed consent form before the patient initiates any study procedure. The subject will receive a 
copy of the IC dated and signed by both parties; the original copy will be kept in the archives 
designated for the study.  

 
 
 
The study flowchart is depicted in Figure 1. Study end points and physiological parameters will be 
monitored and recorded at T0, T1 and T2 (T0=Enrolment, T1 = EIT guided MV at the end of SRM 
trial, and T2 = 24 hours with EIT guided MV as depicted in Figure 2).  
 
4.1 Standard of care treatment in pARDS 
 
In our unit, children with pARDS are ventilated with a lung protective strategy, including small tidal 
volume, high PEEP level and low driving pressure according to ESPNIC guidelines. Baseline 
ventilation is provided using a cuffed endotracheal tube and a leak test is performed before to start 
the study.  Patients will be ventilated with the Dräger Evita Infinity V500 or the Dräger Evita XL 
ventilator (Dräger Medical, Lübeck, Germany) and equipped with the inspiratory and expiratory hold 
pause function. The ventilator will be set in pressure -controlled mode with a target tidal volume of 
6 mL/Kg of Ideal Body Weight. The pediatric ventilation circuit will be  equipped with an y-flow 
sensor for the determination of tidal volume in patients < 10 Kg (18). 
FIO2 will be set to maintain a peripheral oxygen saturation 88%-94%. Respiratory rate will be set at 
25 breaths min with a fixed I:E ratio 1:1.5  to obtain a pH values ranging from 7.25 to 7.40. Plateau 
pressure is maintained below 30 cmH2O during all procedure (19). Inspiratory and expiratory timings 
are set to obtain return to zero flow at end-expiratory. Driving Pressure will be minimized < 15 
cmH2O to maintain lung protective strategy.  
The Acute Respiratory Distress Network (ARDSnet) low-PEEP table will be  used as patients’ safety 
guardrail. The patients receive minimally the lowest PEEP from the low-PEEP table and maximally 
the highest PEEP from the high- PEEP table (Figure 3) (19). 
In severe pARDS patients, esophageal pressure will routinely measured with a radio-opaque 
esophageal balloon (diameter 6 Fr) (CareFusion, Linda, USA) inflated with 0.5–0.8 ml of air 
connected to a pressure transducer. To ensure the correct position of the catheter, the esophageal 
balloon will be positioned in the stomach to check the presence of positive deflection. Then, it will 
be retracted until it reached the lower third of the esophagus; in this position, an inspiratory 

 
 
 
occlusion is made to check for concordant changes in airway and esophageal pressure (20-22). 
During an inspiratory and expiratory pause, the airway and esophageal pressure are measured.  
Transpulmonary pressure wil be computed as the difference between airway and esophageal 
pressure both at end of inspiration and at end of expiration after an inspiratory and expiratory 
occlusion test respectively. 
The respiratory system, lung and chest wall compliance will be computed according to the following 
formula (24): 
 
Respiratory system compliance (Crs) (ml/cmH2O) = tidal volume/(airway pressure at end 
inspiration− airway pressure at PEEP 
 
Respiratory System compliance will be normalized to Ideal Body Weight  (pediatric normal value  
ranging from 1 to 2 ml/cmH2O/Kg). 
 
Lung compliance (C,l) (ml/cmH2O) = tidal volume/(transpulmonary pressure at end inspiration− 
transpulmonary pressure at PEEP) 
 
Chest wall compliance (C, cw) (ml/cmH2O) = tidal volume/(esophageal pressure at end inspiration 
− esophageal pressure at PEEP 
 
Airway driving pressure= airway pressure at end inspiration – airway pressure at PEEP 
 
The standard monitoring in pARDS in our unit includes routinely: 1) Respiratory monitoring: FIO2, 
PEEP, Plateau pressure, Peak Inspiratory Pressure, Mean Airway Pressure, Inspiratory and expiratory 
tidal volume, Inspiratory and expiratory minute ventilation, sidestream capnography,  
transpulmonary pressure derived from the positioning of the esophageal catheter and blood gases 
(arterial or capillary) or transcutaneous gases if is not possible to cannulate radial or femoral artery 
or if controindications to arterial cannulation are present2) Hemodynamic monitoring: EKG, central 

 
 
 
venous pressure, invasive arterial pressure with indwelling arterial catheter, cardiac output 
monitoring, invasive or noninvasive according to clinical conditions 3) Anesthesia and sedation 
monitoring (Bispectral Index) (18). 
 
4.3 Intervention of the study 
 
Eligible patients will be enrolled in the study, if inclusion criteria will be still satisfied before 48 hours 
of mechanical ventilation.  At enrolment, mechanical ventilation will be set according to the 
standard of care criteria mentioned above. EIT parameters, physiological parameters will be 
computed according to Study Flowchart  (T0). 
After enrolment, Intervention of the study will include: EIT measurement, Staircase Recruitment 
Maneuver with EIT guided a decremental PEEP trial; Setting of EIT-guided mechanical ventilation 
(t1); Reevaluation at 24 hours (t2) 
EIT Measurements 
 EIT measurements in children and infants will be performed using the Dräger PulmoVista500 EIT-
device (Dräger Medical GmbH, Lübeck, Germany). The 16-electrode belt will be placed between the 
4th and 5th intercostal space with specific belt according to chest diameter of the child. Ventilator 
data will be continuously recorded by the EIT-device through a serial interface (Medibus, Dräger 
Medical, Lübeck, Germany) from the ventilator. EIT data will be recorded continuously and 
recording will be interrupted only for data transmission and processing. All EIT data processing will 
be performed at the bedside utilizing the EIT easy software application (Dräger Medical GmbH, 
Lübeck, Germany) according to previous study (24). Will be evaluated: Regional Ventilation Delay 
(RVD) = Regional inspiratory delay compared to the global, may indicate atelectrauma, supra-
distention and in general an inhomogeneous ventilation; Global Inhomogeneity Index (GI) = for 
every breathing cycle, a so-called tidal image is generated and each pixel of represents the 
difference in impedance between end-inspiration and end-expiration. The median value of each 

 
 
 
tidal image is calculated for the lung area. The sum of the absolute difference between median value 
and every pixel value is considered to indicate the variation in the tidal volume distribution in the 
whole lung region and it represent the Global Inhomogeneity Index; Geometric Center (GC) = it is 
the weighted mean of row sums obtained from TV image and it indicates ventral-to-dorsal shifts in 
ventilation distribution due to lung opening and closing.  
 
Stepwise Recruitment Maneuver (SRM) with Decremental PEEP trial 
 
Enrolled children with pARDS, will receive SRMs with decremental PEEP trial in presence of:  
Reduction in P/F or S/F ratio > 10% compared to baseline MV set according to NIH protocol (19) 
(due to suctioning, after bronchoscopy or other conditions requiring a transient increase in 
transpulmonary pressure to restore oxygenation). 
SRMs, will be performed in PCV mode with a standardized ventilation protocol. Patient will be 
sedated, paralyzed and ventilated in PCV mode, FIO2 to obtain SPO2> 92%, RR 25, I:E =1:1.5. Alarm 
of pressure limit will be set at 35 cmH2O. The ventilator will be equipped with inspiratory and 
expiratory hold taste. Inspiratory and expiratory occlusion will be held for 5 seconds, data will be 
stored and analyzed with the EVITA V500 own tool. Partitioning of respiratory system mechanics 
will then obtained according to definitions above reported. 
From baseline clinical ventilation, PEEP will be increased in three steps:   8, 10 and 12 cmH2O every 
20  minutes maintaining the following safety termination criteria:  1) maximum plateau pressure 
<30 cmH2O or 2) End Inspiratory Transpulmonary Pressure <28 cmH2O 3) hemodynamic instability 
defined as the need of inotropes/vasopressors. During the Staircase Recruitment Maneuver (SRM), 
the Driving Pressure (DP= plateau pressure - PEEP) will be maintained constant at value <  15 cmH2O 
(25,26). After the stepwise SRM, a decremental PEEP trial will be initiated once a plateau pressure 
of 30 cmH₂O is reached or when end-inspiratory transpulmonary pressure exceeds 28 cmH₂O. After 
reaching either threshold, PEEP will be reduced in three steps to 12, 10, and finally 8 cmH₂O, with 
each step lasting 20 minutes, in accordance with previous studies (24,25). 
4.4  Measurements   

 
 
 
Demographic parameters, comorbidities, factors predisposing to the development of ARDS, 
Pediatric Index of Mortality 2 (PIM2) score, Paediatric Logistic Organ Dysfunction (PELOD) score, 
rescue treatments for ARDS (prone position, high frequency oscillatory ventilation and inhaled nitric 
oxide), 28-day ventilator free days, PICU and Hospital length of stay, PICU and hospital mortality at 
3 and 6 months will be recorded on a dedicated electronic database. 
Haemodynamics and physiological parameters (EKG, invasive arterial pressure, peripheral oxygen 
saturation and end tidal carbon dioxide tension) will be continuously monitored and displayed on a 
multiparametric PICU monitor (Draeger, Lubeck Germany). Blood gases values will be collected from 
arterial catheter (if in place) or from capillary blood samples. SF ratio and trascutaneous gases will 
be considered if controindication to arterial catheter positioninig will be present. 
Data from ventilator will be collected by a USB driver port and downloaded via Medibus cable 
connection on the electronic data chart (Digistat, Acerba Italy) (FiO2, PEEP, tidal volume,  peak and 
mean airway pressure). An indwelling arterial catheter will be routinely inserted to obtain arterial 
blood gas (0.1 mL microsample per measurement) and analyzed in PICU. 
 
5. ENDPOINT 
5.1 Primary endpoint 
The primary end point of the study will be the Global Index (as an index of atelectrauma, supra-
distention and in general an inhomogeneous ventilation)  
 
5.2 Secondary endpoint 
The secondary endpoints encompass the followings:  
• Differences in Tidal Impedance Distribution (TID) at T0, T1  
• Gravity Centre (GC) differences at T0, T1 and  
• RVD40% at T0, T1  
• Respiratory Mechanics at T0, T1  

 
 
 
• Blood gases levels and physiological parameters at T0, T1  
 
6. DURATION/STUDY TIMELINE  
The anticipated duration of the study is 2 years (January 2022- January 2024).  
Enrolment start: January 2025 
Enrolment closure: December 2026 
No further in-hospital or follow-up visits are foreseen. 
 
7. STATISTICAL ANALYSIS  
7.1 Sample size calculation and statistical analysis 
No previous data of similar study are existing, so we calculated the sample size according to clinical 
data obtained in the last months from EIT application in routine clinical practice. 
Considering an α-error = 0.05 and power = 80%, the study would have needed 8 patients to detect 
a 30% reduction in the primary end point, i.e. GI (mean 40± 4SD). Sample size calculation was 
performed  with MedCalc V19.1.7. software (Ltd, Ostend Belgium). 
7.2 Data analysis 
Data Analysis from EIT will take place using a MatLab custom-developed program and the Draeger 
EIT Data Analysis Tool 6.3. Data distribution  will be tested with Shapiro Wilk analysis. Primary and 
secondary endpoints will be then analyzed with parametric or nonparametric ANOVA according to 
data distribution. Frequencies will be compared with chi-square or Fisher exact test, as appropriate. 
A p value less than 0.05 will be considered as significant (MedCalc V19.1.7. Ltd, Ostend Belgium).  
8. ADVERSE EVENTS / DEVICE DEFICIENCIES 

 
 
 
An attending paediatric intensive care physician will always will be present during the study in order 
to identify, report and treat any adverse event arising during the study. 
The protocol will have some determined safety termination criteria aiming to preserve the patients 
from collateral side effects.  
Safety termination criteria includes: Increase in ETCO2 > 10% compared to baseline; Decrease in 
SPO2 > 10% compared to baseline; Hemodynamic instability defined as hypotension and need of 
vasopressors (mean arterial pressure < 20% compared to standard values according to age defined 
values. 
9. RISKS AND BENEFIT EVALUATION 
All parts of the study will be performed under the supervision of an experienced paediatric intensive 
care physician. Any adverse event (see section 8) would be immediately recognized and treated 
adequately. Adverse events could be related to device malfunction or difficult synchronization 
between the ventilator and the patient (subject of the present study).  
Summarizing, the risks related to the protocol refer to device malfunction, which would be 
immediately identified and treated by the attending physician. Furthermore, the protocol will allow 
to identify the ventilatory strategy associated with the best ventilation distribution during MV and 
this, of course, would be a clear clinical benefit both for the studied patients and for future patients 
that could benefit from the acquired knowledge. 
 
10. STUDY MANAGEMENT  
10.1 Collection and management of data  
Information about recruited patients will be entered in a pseudonymised manner into a database 
managed exclusively by the investigator or designated collaborators and such patients will be 
identified by unique code. The file that associates the participant's code with the relevant 
identification data will be stored separately on a password-protected computer. The study database 

 
 
 
will be password protected and uploaded to a computer that is also password protected and 
accessible only to study personnel designated by the principal investigator. The de-identification of 
the data will take place in such a way that the people who access the database will not be able to 
trace in any way the identity of the subjects. Only local investigators will be able to trace the identity 
of the enrolled subjects. 
EIT data will be saved on EIT hardware (Drager Pulmovista 500) and on a USB driver anonymously.  
10.2 Regulatory aspects and ethical considerations  
10.2.1 Approval of the Competent Authority 
In accordance with current regulations, the principal investigator must obtain approval from the 
appropriate Competent Authority before starting the clinical study. 
The present study will be conducted in accordance with the rules of the ICH / GCP (International 
Conference of Harmony / Good Clinical Practice) and all applicable laws, including the Helsinki 
Declaration of June 1964, amended by the latest World Medical Association General Assembly in 
Seoul, 2008 
10.2.2 Approval of the Ethics Committee 
The investigator must ensure that the protocol has been evaluated and approved by the Local 
Independent Ethics Committee (EC) before starting the study. 
The EC must also verify and approve the informed consent form (IC) and all written information that 
the patient receives before the enrolment in the study 
Should the protocol and / or IC need to be changed during the study it will responsibility of the 
principal investigator to ensure that the changes are reviewed and approved by the EC 
The content of these changes will be implemented only after the EC has approved them. Until that 
time, it will be necessary to refer to the previous version of the document already approved. 

 
 
 
10.2.3 Informed consent (IC) 
The investigator has the task of informing the patients and parents about all aspects and procedures 
of the study. In his absence, the following persons will be responsible for informing parents and 
mature patients about all aspects and procedures of the study. 
Dr.ssa Giovanna Chidini, Dr.ssa Cinzia Montani, Dr.ssa Tiziana Marchesi, Dr. Stefano Scalia 
Catenacci, Dr.ssa Giada Donà, Dr.ssa Ludovica Ughi, Dr.ssa Lucia Orlandi, Dr. Giovanni Babini, dr.ssa 
Maria Adele Figini. 
The process for obtaining the informed consent must comply with the regulatory procedures in 
force. The investigator (or a designated collaborator) and the subject must date and sign the 
informed consent form before the patient initiates any study procedure. The subject will receive a 
copy of the IC dated and signed by both parties; the original copy will be kept in the archives 
designated for the study. Neither the investigator nor the designated personnel should in any way 
exercise any coercion or influence on a subject to induce her/him to participate or continue to 
participate in the study. The decision of a subject to participate in the study must be completely 
voluntary.  
10.3 Duties of the experimenter 
According to the local regulations, the investigator must send periodic reports regarding the 
progress of the study in his centre to the EC and notify the closure of the study. Periodic reports and 
notification of study closure are part of the investigator's responsibilities 
10.4 Study monitoring 
According to local regulations and Good Clinical Practice (GCP), the monitor must visit or periodically 
contact the centre. The duration, nature and frequency of these visits / contacts depend on the 
recruitment frequency, the quality of the documents held by the centre and from their adherence 
to the protocol. 
 
Through these contacts, the monitor must: 

 
 
 
• monitor and evaluate the progress of the study 
• examine the data collected 
• conduct verification of the source document 
• identify any problems and their solutions 
The purposes of the monitoring activity are to verify that: 
• the subject's rights and well-being are respected 
• the data of the study are accurate, complete and verifiable from the original documents 
• the study is conducted in accordance with the protocol and any approved amendments, GCP and 
applicable regulations. 
 
The experimenter must: 
• give the monitor direct access to all relevant documentation 
• dedicate part of his time and his staff to the monitor to discuss the monitoring results and any 
other possible aspects. 
 
The monitor must also contact the centre before the study begins to discuss the protocol and data 
collection procedures with the staff. 
10.5 Quality assurance of the study 
As a promoter of the study, IRCCS Ca 'Granda Foundation, Ospedale Maggiore Policlinico can carry 
out a quality control of the study at its discretion. In this case, the investigator should allow the 
monitor to access all relevant documentation directly and spend part of her/his time and staff on 
the auditor to discuss the monitoring results and any other aspects of the study. 
Furthermore, the Regulatory Authorities can carry out inspections. In this case, the investigator 
must authorize the inspector to have direct access to all relevant documentation, and to devote 
part of her/his time and staff to the inspector himself to discuss the monitoring results and any 
other aspects of the study. 

 
 
 
10.6 Study closure 
At study closure, the monitor and the investigator must activate a series of procedures: 
• review all the study documentation 
• reconcile study data 
• reconcile all the clarification reports. 
10.7 Archiving of documents 
In accordance with current national regulations, the investigator must keep a copy of all the 
documentation and keep it in a dry and safe place after closing the study. 
10.8 Disclosure of information concerning scientific discovery 
10.8.1 Confidentiality 
The investigator and other personnel involved in the study must process all the information related 
to the study (including the protocol, data obtained and all the documentation produced during the 
study) and must not use such information, data or relationships for purposes other than those 
described in the protocol.  
These restrictions do not apply to 
1) Information that becomes publicly available, not due to negligence on the part of the investigator 
or his staff 
2) Information requiring the disclosure reserved to EC for the sole purpose of evaluating the study 
3) Information that must be disclosed to obtain adequate medical treatment for a study subject 
10.8.2 Publications 
The IRCCS Ca 'Granda Foundation, Ospedale Maggiore Policlinico is the sole owner of the data. 
 
11. ALLOWANCES AND COMPENSATION FOR DAMAGE 

 
 
 
In the event of undesired events or any damage that may result from participation in the research, 
the Insurance Policy of our Institute is also extended to cover the subjects participating in the 
research projects 
12. PROTOCOL AMENDMENTS 
Not applicable to the present study. 
13. FINANCIAL AGREEMENTS 
Not applicable to the present study. 
14. DISCLOSURES ON CONFLICTS OF INTEREST 
No conflict of interest related to the present study 
 

 
 
 
15. REFERENCES 
1 
Brower RG, Matthay MA, Morris A, et al; Acute Respiratory Distress Syndrome Network: 
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung 
injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342:1301–1308 
 
2 
Briel M, Meade M, Mercat A, et al: Higher vs lower positive end-expiratory pressure in patients 
with acute lung injury and acute respiratory distress syndrome: Systematic review and meta-
analysis. JAMA 2010 303:865–873 
 
3 
Wiedemann HP, Wheeler AP, Bernard GR, et al: Comparison of two fluid-management 
strategies in acute lung injury. N Engl J Med 2006; 354:2564–2575 
 
4 
Wolf GK, Gómez-Laberge C, Kheir JN, et al: Reversal of dependent lung collapse predicts 
response to lung recruitment in children with early acute lung injury. Pediatr Crit Care Med 
2012; 13:509–515 
 
5 
Gattinoni L, Caironi P, Cressoni M, et al: Lung recruitment in patients with the acute respiratory 
distress syndrome. N Engl J Med 2006; 354:1775–1786 
 
6 
Papazian L, Forel JM, Gacouin A, et al; ACURASYS Study Investigators: Neuromuscular blockers 
in early acute respiratory distress syndrome. N Engl J Med 2010; 363:1107–1116 
7 
Gattinoni L, Tognoni G, Pesenti A, et al; Prone-Supine Study Group: Effect of prone positioning 
on the survival of patients with acute respiratory failure. N Engl J Med 2001; 345:568–573 
 
8 
Guérin C, Reignier J, Richard JC, et al; PROSEVA Study Group: Prone positioning in severe acute 
respiratory distress syndrome. N Engl J Med2013; 368:2159–2168 
 

 
 
 
9 
Victorino JA, Borges JB, Okamoto VN, et al: Imbalances in regional lung ventilation: A validation 
study on electrical impedance tomography. Am J Respir Crit Care Med 2004; 169:791–800 
 
10 Wrigge H, Zinserling J, Muders T, et al: Electrical impedance tomography compared with 
thoracic computed tomography during a slow inflation maneuver in experimental models of 
lung injury. Crit Care Med 2008; 36:903–909 
 
11 Wolf GK, Gómez-Laberge C, Rettig JS, et al: Mechanical ventilation guided by electrical 
impedance tomography in experimental acute lung injury. Crit Care Med 2013; 41:1296–1304 
 
12 Eckhard Teschner, Michael Imhoff, Steffen Leonhardt (2010). Electrical Impedance Tomography: 
The realisation of regional ventilation monitoring. Lubecca: Drägerwerk AG & Co. KGaA. 
 
13 Alessandro Santini A., Elena Spinelli E., Thomas Langer T., Savino Spadaro S., Giacomo Grasselli 
G., Tommaso Mauri T. (2018). Thoracic electrical impedance tomography: an adaptive monitor 
for dynamic organs. Journal of Emergency and Critical Care Medicine, 2:71. doi: 
10.21037/jeccm.2018.08.08. 
 
 
14 Zhao Z., Moller K., Steinmann D., Frerichs I., Guttmann J. (2009). Evaluation of an electrical 
impedance tomography-based global inhomogeneity index for pulmonary ventilation 
distribution. Intensive Care Medicine, 35:1900–1906. DOI 10.1007/s00134-009-1589-y 
 
15 Sobota V., Roubik K. (2016). Center of Ventilation—Methods of Calculation using Electrical 
Impedance Tomography and the Influence of Image Segmentation. In XIV Mediterranean 
Conference on Medical and Biological Engineering and Computing. pp. 1258-1269.  
 

 
 
 
16 Spinelli E., Mauri T., Fogagnolo A., Scaramuzzo G., Rundo A., Grieco D.L., Grasselli G., Volta C.A., 
Spadaro S. (2019). Electrical impedance tomography in perioperative medicine: careful 
respiratory 
monitoring 
for 
tailored 
interventions. 
BMC 
Anesthesiology, 
19:140. 
https://doi.org/10.1186/s12871-019-0814-7  
 
17 Pediatric Acute Respiratory Distress Syndrome. Pediatric Critical Care Medicine, 2005; 16: 428–
439. doi:10.1097/pcc.0000000000000350PALICC ARDS  
 
18 Kneyber, M. C. J., de Luca, D., Calderini, E., Jarreau, P.-H., Javouhey, E., Rimensberger, P. C. 
(2017). Recommendations for mechanical ventilation of critically ill children from the Paediatric 
Mechanical Ventilation Consensus Conference (PEMVECC). Intensive Care Medicine, 43(12), 
1764–1780. doi:10.1007/s00134-017-4920-z 
 
19 National Heart, Lung, and Blood Institute ARDS Clinical Trials Network: Mechanical Ventilation 
Protocol Summary. 2008. Available at: hiip:// 
www.ardsnet.org/files/ventilator_protocol_2008-07.pdf. Accessed 
 
20 Chiumello D, Carlesso E, Cadringher P, Caironi P, Valenza F, Polli F, Tallarini F, Cozzi P, Cressoni 
M, Colombo A, Marini JJ, Gattinoni L. Lung stress and strain during mechanical ventilation for 
acute respiratory distress syndrome. Am J Respir Crit Care Med. 2008;178:346–55 
 
 
21 Protti A, Cressoni M, Santini A, Langer T, Mietto C, Febres D, Chierichetti M, Coppola S, Conte G, 
Gatti S, Leopardi O, Masson S, Lombardi L, Lazzerini M, Rampoldi E, Cadringher P, Gattinoni L. 
Lung stress and strain during mechanical ventilation: any safe threshold? Am J Respir Crit Care 
Med. 2011;183:1354–62. 
 

 
 
 
22 Chiumello D, Cressoni M, Colombo A, Babini G, Brioni M, Crimella F, Lundin S, Stenqvist O, 
Gattinoni L. The assessment of transpulmonary pressure in mechanically ventilated ARDS 
patients. Intensive Care Med. 2014;40(11):1670–8 
 
23 Turner, D. A., Heitz, D., Zurakowski, D., & Arnold, J. H. (2009). Automated measurement of the 
lower inflection point in a pediatric lung model*. Pediatric Critical Care Medicine, 10(4), 511–
516. doi:10.1097/pcc.0b013e3181a0e274  
 
24 Rosemeier, I., Reiter, K., Obermeier, V., & Wolf, G. K. (2019). Mechanical Ventilation Guided by 
Electrical Impedance Tomography in Children With Acute Lung Injury. Critical Care Explorations, 
1(7), e0020. doi:10.1097/cce.0000000000000020 
 
25 Cruces, P., Donoso, A., Valenzuela, J., & Díaz, F. (2012). Respiratory and hemodynamic effects 
of a stepwise lung recruitment maneuver in pediatric ARDS: A feasibility study. Pediatric 
Pulmonology, 48(11), 1135–1143. doi:10.1002/ppul.22729 
 
26 Amato, M. B. P., Meade, M. O., Slutsky, A. S., Brochard, L., Costa, E. L. V., Schoenfeld, D. A. 
Brower, R. G. (2015). Driving Pressure and Survival in the Acute Respiratory Distress Syndrome. 
New England Journal of Medicine, 372(8), 747–755. doi:10.1056/nejmsa1410639 
 
27 Stapleton, R. D., Suratt, B. T., Neff, M. J., Wurfel, M. M., Ware, L. B., Ruzinski, J. T, Parsons, P. 
E. (2019). Bronchoalveolar Fluid and Plasma Inflammatory Biomarkers in Contemporary ARDS 
Patients. Biomarkers, 1–25. doi:10.1080/1354750x.2019.1581840 
 
 
 
 
 

 
 
 
FIGURES  
 
 
 
Figure 1. PALICC Criteria for pARDS  
 
 
 
 
 

 
 
 
Figure 2. Study Flowchart 
  
MV Mechanical Ventilation; PEEP Positive End Expiratory Pressure; PCV Pressure Controlled 
Ventilation ;  Crs Respiratory System Compliance;  Clung Lung compliance; CCW Chest Wall 
Compliance, PES Esophageal Pressure; EIT Electro Impedance Tomography;  RVD Regional Ventilator 
Delay; GI Global Inhomogeneity Index;  DP Driving Pressure;  SRM Stepwise  Recruitment Maneuver.  
T0 Baseline measurement at enrolment; T1 End of  SRM trial; T2 End of the study at 24 hours  
 
 

 
 
 
Figure 3. NIH PEEP/FiO2 Table