Electrical Impedance Tomography vs Dynamic Compliance Guided Positive End-expiratory Pressure Titration During Laparoscopic Gynecological Surgery: A Multi-center, Prospective Randomized Trial - TITRANT
Phase: NA
Conditions: Mechanical Power, Postoperative Pulmonary Complications (PPCs), Oxygenation
Sponsor: Pest County Flór Ferenc Hospital

 
ElecTrical Impedance TomogRaphy vs dynamic compliANce 
guided positive end-expiratory pressure Titration during 
laparoscopic gynaecological surgery: A multi-centre, prospective 
randomized trial – TITRANT Trial 
 
 
STUDY PROTOCOL WITH SAP 
 
Approval Number: BM/8893-3/2025 
 
 
Last updated on March 12, 2025 
 
 
 
 
 
 
 
 
 
 
 
 

 
STUDY PROTOCOL 
 
Title of the Study 
ElecTrical Impedance TomogRaphy vs dynamic compliANce guided positive end-expiratory 
pressure Titration during laparoscopic gynaecological surgery: A multi-centre, prospective 
randomized trial – TITRANT Trial  
 
 
PICO 
P 
Titrating PEEP - in order to determine individually optimal PEEP levels to reduce the 
mechanical power responsible for lung injury is one of the main targets of personalised 
mechanical ventilation, however there is no recommendation about best practice 
I 
EIT-guided decremental PEEP titration during laparoscopic gynaecological surgery 
C 
Cdyn-guided decremental PEEP titration during laparoscopic gynaecological surgery 
O 
Mechanical Power (MP), Postoperative Pulmonary Complications (PPCs), intra- and 
postoperative oxygenation indicated by PaO2/FiO2, driving pressure (dP), Positive End-
Expiratory Pressure (PEEP), dynamic compliance (Cdyn), Global Inhomogeneity Index 
(GI), Overdistension/Collapse (ODCL)  
 
 
Background 
Despite both surgical and anaesthesia related risk factors of postoperative pulmonary 
complications (PPCs) are well known, PPCs occur frequently with an incidence of 5% to 33%, 
resulting in a 30-day mortality of about 20% in the affected patient population.1-3 
Mechanical ventilation as a major risk factor plays a pivotal role in the development of PPCs, 
however, it is mandatory during laparoscopic surgeries under general anaesthesia. 
Mechanical ventilation alone alters the excursion of the diaphragm resulting a ventral 
redistribution of ventilation, additionally, the increased intraabdominal pressure due to the 
pneumoperitoneum and Trendelenburg position during laparoscopy leads to a cephalad shift 

of the diaphragm decreasing the functional residual capacity and elevating the 
transpulmonary pressure (PTP). Moreover, evidence exist, that inappropriate ventilatory 
parameters may lead to physical (volu-, baro- and atelectrauma) and biological damage of the 
lungs (summarized as ventilator-induced lung injury, VILI) causing PPCs accounting for 
substantial morbidity and mortality.4 Recent research have suggested the importance of 
individual lung protective ventilation (LPV) applying low tidal volumes (VT), optimal positive 
end-expiratory pressure (PEEPopt), alveolar recruitment manoeuvres (ARMs) and limited 
plateau (Pplat < 25 cmH2O), driving (dP < 15 cmH2O) and transpulmonary pressures (PTP < 20 
cmH2O) in order to reduce the risk of VILI, even in patients with healthy lungs, however, results 
remained controversial, and the incidence of PPCs has not decreased significantly.5-11 
Respiratory system is complex, its reactions and tolerance to the effects of positive pressure 
mechanical ventilation are extremely individual, therefore focusing on separated ventilatory 
parameters does not lead to favourable clinical improvement and outcomes. 
Low VT (4-6 mL/kg Ideal Body Weight, IBW) is a useful tool to prevent volutrauma but may 
result in increased dead space, atelectasis and hypercapnia. In this scenario increasing 
respiratory rate (RR) can reduce arterial carbon-dioxide tension (PaCO2), however, too short 
expiratory time may increase intrinsic PEEP resulting air trapping, and hyperinflation of the 
lungs may occur. Estimating the end-inspiratory PTP by measuring oesophageal pressure thus 
determining individually appropriate VT can eliminate these obstacles, however it is too 
expensive for everyday use. 
Applying PEEPopt may prevent atelectasis and cyclic lung collapse (cyclic opening and closing 
of alveoli). On the other hand, high PEEP may lead to barotrauma, ventilation-perfusion 
mismatch and haemodynamic compromise can develop due to a high intrathoracic pressure.12 
Several methods exist to determine PEEPopt. It can be titrated applying respiratory mechanics 
parameters (static or dynamic pulmonary compliance, Cstat / Cdyn; dead space fraction; end-
expiratory PTP; dP) or bedside visualization of the lungs using ultrasound (US) or electrical 
impedance tomography (EIT) can be another option. Main concerns about the use of basic 
respiratory mechanics parameters are that neither overdistension of the lungs, nor 
distribution of ventilation cannot be measured. However, dP – calculated as the difference 
between Pplat and PEEP (dP = Pplat - PEEP) – seems to be an important safety parameter to 
determine appropriate PEEP and VT, and may decrease the incidence of PPCs as compared to 
conventional LPV.13 

Bedside visualization of the lungs by US is useful, however appropriate practice and 
experience are required for proper assessment. Moreover, it only provides intermittent 
evaluation, while performing US imaging during surgery may be cumbersome and time 
consuming. 
EIT provides a non-invasive, radiation-free, real time, continuous monitoring, that identifies 
changes in lung impedance which corresponds to lung volume. Besides these advantages, EIT 
imaging gives the opportunity to optimize PEEP by visualizing the distribution of ventilation, 
and to distinguish recruitment from overdistension. The global inhomogeneity index (GI) 
quantifies the homogeneity of the tidal volume distribution. It correlates with lung 
recruitability and may guide ventilatory settings in order to optimise alveolar 
homogeneity.14,15 During an EIT-guided titration procedure, regional overdistension (OD) and 
alveolar collapse (CL) can be quantified (ODCL), and PEEPopt is considered as the intersection 
between the lower percentage of overdistension and collapse.16-18 Optimizing PEEP using EIT 
to counterbalance the effects of laparoscopic procedures has some rational as indicated in a 
previous trial.19 
ARMs are the most controversial components of the LPV concept, as it is obvious that not all 
lungs are recruitable, while ARMs can cause severe haemodynamic instability especially in 
hypovolaemic patients. Despite they may improve oxygenation and reverse atelectasis by 
opening collapsed alveoli, there is no recommendation about their exact role and use.1 
Recognizing these issues, a new conceptional direction emerged in the last few years by 
evaluating the potential role of the amount of energy transferred to the lung parenchyma per 
unit of time (J/min) during mechanical ventilation.20,21 This energy is called mechanical power 
of ventilation (MP), and recent trials found correlation between high MP values (MP > 12 
J/min) and the severity of VILI both in critically ill patients with ARDS and patients with non-
injured lungs as well.22-26 MP integrates the major components of positive pressure ventilation 
that drive VILI (static, dynamic and resistive, related to PEEP, dP, flow and airway resistance 
respectively; and respiratory rate), thus gives the opportunity to balance the effects of each 
respiratory parameters. Theoretically, reducing MP below the safety threshold may be the 
main goal of the LPV strategy. Due to the original equation is very sophisticated and difficult 
to calculate, a surrogate formula was established including RR, VT, peak inspiratory pressure, 
PEEP and Pplat: MP = 0.098 x RR x TV (L) x [Ppeak – ½ x (Pplat – PEEP)]. These parameters can 
be acquired from the ventilators of all anaesthesia machines, thus MP can be easily calculated 

during surgery.27 It is important to notice, that VT is a predominant parameter in the formula, 
while PEEP is a double-edged sword. Inappropriate PEEP may increase MP, whereas optimal 
PEEP can decrease it by improving pulmonary compliance. Neglecting the role of respiratory 
rate is common in terms of the genesis of VILI, however it is obvious that it has a linear 
correlation with MP, that should be taken in account. Despite the robust pathophysiological 
rational of implementing MP as a goal of LPV, some limits must be emphasized. First, 
validation of its use in the surgical population is still lacking. Second, due to the complexity of 
the interaction between the respiratory parameters and inhomogeneities in the distribution 
of ventilation (atelectasis and hyperinflation may be present at the same time in different lung 
areas), local lung tissue injury may still develop.28  
The aim of our study is to compare the effects of two different PEEP titrating methods (EIT-
guided vs Cdyn-guided) on mechanical power of ventilation, oxygenation, respiratory 
mechanics 
parameters, 
global 
inhomogeneity 
index, 
overdistension/collapse 
and 
postoperative pulmonary complications in patients with non-injured lungs undergoing 
laparoscopic gynaecological surgery. Despite Cdyn-directed LPV has several proven 
advantages, we hypothesize that optimizing intraoperative mechanical ventilation using EIT-
guided PEEP titration may further improve patient outcomes by reducing mechanical power 
responsible for VILI and consequent PPCs. These anticipated advantages may improve our 
knowledge about individualized protective ventilation, enhance postoperative recovery, 
shorten in-hospital stay and reduce healthcare related costs. 
 
 
Methods and design 
Objectives of the study 
The aim of the study is to compare the effects of two different PEEP titrating methods on 
mechanical power of ventilation, oxygenation, respiratory mechanics parameters and 
postoperative pulmonary complications in patients with non-injured lungs undergoing 
laparoscopic gynaecological surgery. 
 
 
Study endpoints 

Primary endpoints: 
• Mechanical power of ventilation (MP; J/min) 
o MP will be calculated using a comprehensive formula for volume-controlled 
ventilator mode 
▪ MP = 0.098 x RR x TV (L) x [ Ppeak – ½ x (Pplat – PEEP)] 
Secondary endpoints: 
• Oxygenation (PaO2 / FiO2) 
• PEEP 
• Cdyn 
• Driving pressure 
• PPCs within 48 hours after surgery 
o atelectasis detected on computed tomography or chest radiograph, 
o pneumonia, 
o Acute Respiratory Distress Syndrome, 
o pulmonary aspiration (clear clinical history AND radiological evidence) 
 
Tertiary endpoints: 
• length of hospital stay (days) 
• in-hospital mortality 
• 28-day mortality 
• adverse events related to the PEEP titrating procedure 
 
Study design 
Multi-centric, 
double-arm, 
parallel-group, 
single-blinded 
(subject), 
interventional, 
prospective, randomized controlled trial.  
 
Participating Centres 
Number 
Centre Data 
1 
Flór Ferenc Hospital Kistarcsa, Hungary 
2 
Semmelweis University, Hungary 
3 
Semmelweis Hospital Kiskunhalas, Hungary 

SPIRIT  
 
STUDY PERIOD 
 
Enrolment 
Allocation 
Post-allocation 
Follow up 
TIMEPOINT** 
-2/1 week 
-t1 
0 
DOS 
POD1 
POD2 
POD3-28 
ENROLMENT: 
 
 
 
 
 
 
 
Preoperative assessment 
(pre-screening) 
X 
 
 
 
 
 
 
Eligibility screen 
 
X 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
Allocation 
 
 
X 
 
 
 
 
INTERVENTIONS: 
 
 
 
 
 
 
 
PEEP-EIT 
 
 
 
X 
 
 
 
PEEP-Cdyn 
 
 
 
X 
 
 
 
ASSESSMENTS: 
 
 
 
 
 
 
 
Mechanical power 
 
 
 
X 
 
 
 
Oxygenation (PaO2/FiO2) 
 
 
 
X 
 
 
 
PEEP 
 
 
 
X 
 
 
 
Cdyn 
 
 
 
X 
 
 
 
Driving pressure 
 
 
 
X 
 
 
 
EIT parameters 
(TVROI3-4, EELV, GI, ODCL) 
 
 
 
X 
 
 
 
Postoperative pulmonary 
complications 
 
 
 
X 
 
 
 
SOFA Score 
 
 
 
X 
 
 
 
In-hospital stay 
 
 
 
 
 
 
 
In-hospital mortality 
 
 
 
X 
 
 
 
28-day mortality 
 
 
 
X 
 
 
 
Adverse events 
 
 
 
X 
 
 
 
 

Blinding, data collection, randomization and record-keeping 
Patient data, intra- and postoperative measurements, respiratory parameters, laboratory 
results, and clinical status (SOFA Score) will be collected onto Case Report Forms (CRF). CRF 
and patient evaluation chart will not be assessed in front of the patient. 
Participants will be randomized to two interventional groups in a ratio of 1:1. Randomization 
will be carried out by a computer-generated blocked randomization list with 20 blocks of 10 
patients per block. Allocation will be stored in sealed opaque and numbered envelopes. 
Participants will be included and allocated in numerical order. 
 
Selection of the participants 
Inclusion criteria: 
• Patient scheduled for elective laparoscopic gynaecological surgery 
• Age > 18 years 
• Signed consent to participate in the trial 
  
Exclusion criteria: 
• Age < 18 years 
• ASA physical status IV 
• History of severe restrictive or chronic obstructive pulmonary disease (COPD, GOLD 
grades III or IV) 
• Uncontrolled bronchial asthma 
• Pulmonary metastases 
• History of any thoracic surgery 
• Need for thoracic drainage before surgery 
• Congestive heart failure (NYHA grades III or IV) 
• Extreme obesity (BMI>35 kg m-2) 
• Lack of patient’s consent. 
 
 
 
 

Study Protocol 
Time course of the study 
Preoperative assessment and admission 
During standard institutional preoperative assessment patient’s eligibility for laparoscopic 
gynaecological surgery will be evaluated. Medical history, laboratory and chest X-ray or CT 
scan, 12-lead ECG, ASA physical status, BMI, postoperative respiratory failure risk assessment 
(RFRI and ARISCAT), nutritional risk screening (NRS 2002 tool) and if required (in case of history 
of smoking or coronary artery disease) results of spirometry, echocardiography and ergometry 
will be recorded. Participants fulfilling the inclusion criteria will be asked for their signed 
informed consent. 
After admission to the Department of Gynaecology (on the day before surgery) patient will be 
randomized into one of the study groups.  
 
Intraoperative care 
Before induction of anaesthesia an arterial cannula will be inserted for invasive arterial blood 
pressure monitoring and blood gas sampling while an EIT belt (Dräger PulmoVista 500) will be 
placed between the 4th and 6th intercostal space according to the manufacturer's 
recommendation. 
Immediately after induction of anaesthesia and orotracheal intubation, once a steady state 
has been reached (Table 2), all patients will be submitted to an ARM using the sustained 
airway pressure by the CPAP method, applying 30 cmH2O PEEP for 30 seconds. After ARM, 
PEEP will be set to 6 cmH2O in both groups and LPV (TV = 6 mL/Kg IBW, FiO2 = 0.4) will be 
performed. 
After pneumoperitoneum (maximal intraabdominal pressure = 12 cmH2O) and Trendelenburg 
position (35°) optimal PEEP (PEEP-EIT) will be determined during a decremental PEEP titration 
procedure using the PEEP Trial Diagnostic Tool of the EIT device in the PEEP-EIT group. During 
the procedure Cdyn values and belonging PEEP levels will also be recorded. In the PEEP-C 
group, optimal PEEP will be determined using Cdyn values: the highest achievable Cdyn will 
determine the optimal level of PEEP (PEEP-C). EIT parameters will also be recorded. During 
surgery ARM will be repeated and arterial blood gas samples (ABGs) will be evaluated every 

30 minutes. In case of decreasing oxygen saturation (SpO2 < 92%) a rescue ARM will be 
performed using FiO2 of 1.0. 
To maintain anaesthesia, in both groups a target-controlled infusion regimen (propofol – 
remifentanil) will be performed during surgery. Depth of anaesthesia will also be monitored.  
 
Steady state after induction of anaesthesia 
Haemodynamics 
 
Mean arterial pressure 
65-90 mmHg 
Heart Rate 
50-100 min-1 
Ventilation 
 
SpO2 
≥ 96 % 
EtCO2 
35-45 mmHg 
Depth of anaesthesia 
 
Entropy 
40-60 
BIS 
40-60 
PSI 
25-50 
SpO2, EtCO2, BIS, PSI 
 
Arterial blood pressure, heart rate (HR) and end-tidal carbon dioxide tension (EtCO2) will be 
monitored continuously. Cdyn, core temperature and train-of-four relaxometry data will be 
recorded every 15 minutes. 
During surgery, in cases of hypotension vasopressor treatment (ephedrine, phenylephrine, 
norepinephrine) will be started to maintain mean arterial pressure above 65 mmHg. For 
intraoperative fluid management patients will receive a 2 mL/Kg/h of balanced crystalloid 
solution until the end of surgery. In cases of bleeding crystalloid substitution will be given. 
Packed red blood cell (PRBC) transfusion will be given whenever the attending anaesthetist 
renders it necessary (Figure 2). 
 
 
 
 
 

Protocol of intraoperative interventions 
 

Postoperative care 
After extubation, patients will be admitted to the Post-Anaesthesia Care Unit. ABGs will be 
collected and evaluated for PaO2/FiO2 30 minutes, 6, 12, 24 and 48 hours after surgery. At the 
same timepoints EIT measurements including mid-dorsal and dorsal and regions of interest 
(TVROI3, TVROI4) and end-expiratory lung volume (EELV) will also be performed and recorded. 
On the first postoperative day (24 hours after surgery), a chest X-ray will be performed and 
repeated on the following days if developing of pulmonary complications were suspected. 
Chest X-ray will be evaluated by an independent trained radiologist who will not be involved 
in the study. Postoperative analgesia will be based on institutional protocol. 
Patients' clinical progress will be monitored by daily SOFA Scores, laboratory and physical 
examinations. 
From postoperative day 3 (POD 3 – POD 28, follow-up) 
During follow-up period, secondary endpoints, in-hospital stay, 28-days and in-hospital 
mortality will also be evaluated. 
Figure 3 shows the CONSORT flowchart of the trial. 
 
CONSORT flowchart of the trial 
 
 
Assess for eligibility 
Excluded 
   Not meeting inclusion criteria 
   Declined to participate 
   Other reasons 
Analysed 
 Excluded from analysis 
Lost to follow-up 
Discontinued intervention 
 
Allocated to PEEP-EIT Group 
Lost to follow-up 
Discontinued intervention 
 
Allocated to PEEP-Cdyn Group 
Analysed   
 Excluded from analysis 
Allocation 
Analysis 
Follow-Up 
Randomization (n=200) 
Enrollment 

Study arms and assigned intraoperative interventions 
A total number of 200 patients scheduled for laparoscopic gynaecological surgery will be 
enrolled in this study. An equal number of patients will be randomized into the PEEP-EIT and 
PEEP-C groups. 
Patients randomized into the PEEP-EIT group undergo an ARM using the sustained airway 
pressure by the CPAP method, applying 30 cmH2O PEEP for 30 seconds followed by a 
decremental PEEP titration procedure directed by EIT PEEP Trial of the PulmoVista 500 device. 
During the PEEP titration procedure, PEEP will be decreased from 18 cmH2O by 2 cmH2O every 
20 ventilatory cycles, until a final PEEP of 6 cmH2O. On each level of PEEP Cdyn values will also 
be recorded. Optimal PEEP is considered as the intersect between the lower percentage of 
overdistension and collapse, based on the diagnostic tool of the EIT device. After PEEP titration 
procedure, a lung protective mechanical ventilation will be performed using PEEPopt (PEEP-
EIT) and low tidal volumes. 
Patients randomized into PEEP-C group will undergo the same ARM followed by a decremental 
PEEP titration procedure directed by Cdyn. During the PEEP titration procedure, PEEP will be 
decreased from 18 cmH2O by 2 cmH2O every 20 ventilatory cycles, until a final PEEP of 6 
cmH2O. On each level of PEEP EIT measurements will also be recorded. Optimal PEEP is 
considered as the PEEP value resulting the highest possible Cdyn measured by the ventilator. 
After PEEP titration procedure, a lung protective mechanical ventilation will be performed 
using optimal PEEP and low tidal volumes. ARMs will be performed every 30 minutes in both 
groups. 
MP, dP, Cdyn, TVROI3, TVROI4 and EELV will be recorded immediately after the PEEP titration 
trial and every 15 minutes during surgery in both groups. 
Oxygenation and dead space fraction indicated by PaO2/FiO2 and (a-Et)PCO2, respectively will 
recorded every 30 minutes during surgery in both groups. PaO2/FiO2 will be recorded 
immediately after extubation, 30 mins, 2, 6, 12, 24 and 48 hours after extubation also. 
GI and ODCL will be evaluated retrospectively after surgery using the EIT Diag SW 1.6 
diagnostic software for Dräger PulmoVista 500. 
 
 
 

Data monitoring 
Data monitoring will be performed centrally for quality control purposes by an external, 
independent doctor, who will not be involved in the study. Monitoring will evaluate the 
progress of the study, and verify the accuracy and completeness of data recording (eCRF, 
source data, informed consent forms and outcome variables). 
 
Statistical analysis 
The sample size was estimated for the secondary endpoint, the Cdyn. In a previous study 
conducted by Shu et al, a difference of 4.5% was found regarding the Cdyn (66.3 ± 10.66 
mL/cmH2O vs 61.8 ± 11.03 mL/cmH2O) between the PEEP-Cdyn and PEEP-EIT groups.29 A 
sample size of 200 patients (100 patients in each arm) will be needed to observe this 
difference, assuming α = 0.05 and power of 80% and considering a data loss of 10%. 
Data will be analysed by the research team in collaboration with a medically versed 
biostatistician after completion of the trial. There will be no interim analysis. Statistical 
analysis will be conducted on an intention-to-treat basis. 
It is expected that the majority of source data will be recorded onto eCRFs, nonetheless before 
starting the data analysis, the missing-data mechanism and pattern will be evaluated and 
these findings will be used to determine whether they have impact on statistical analysis and 
results and how they can be managed. 
Data distribution will be tested by the Kolmogorov-Smirnov analysis. Normally distributed 
data will be presented as mean and standard deviation (SD) and skewed data as median 
(interquartile range). Comparing related samples, the paired and unpaired Student t-test will 
be used for normally distributed data and the Wilcoxon signed rank test and Mann-Whitney 
U-test for skewed data. Differences in proportions will be evaluated using the Fisher’s exact 
test, and risk ratio with associated 95% confidence interval (CI). 
Two-way repeated-measures analysis of variance (2-way RM ANOVA) will be used to compare 
the groups MP levels. Relationship between MP levels and PPCs will be evaluated using the 
Pearson correlation. Statistical analysis of SOFA scores, in-hospital stay, readmission rate, in-
hospital and 28-days mortality data of groups will be implemented by the chi-square test. P 
value of less than 0.05 will be considered significant. 
 

Adverse events and interruption of the trial 
Every patient included in the trial will receive daily visits from intensive care therapist and 
gynaecologist in charge from POD 1 until leaving the hospital. The study nurse will be 
responsible for collecting blood samples and record relevant required data onto eCRFs. During 
out-of-hospital follow-up period (until POD 28) patients’ progress, respectively deterioration 
will be checked by daily phone call visits. 
Investigators will monitor the patients for any adverse events (AEs), which are defined as 
severe or prolonged hypotension (systolic blood pressure < 90 mmHg) and significant cardiac 
arrhythmias associated with the PEEP titration procedure. AEs will be documented on the 
eCRF and the principal investigator will be informed. 
Serious adverse events (SAEs) are defined as severe barotrauma leading to pneumothorax, 
significant prolongation of hospitalization, persistent or significant disability or incapacity, and 
severe deterioration (life-threatening state or even death) associated with the PEEP titration 
procedure. All treatment related SAEs will be recorded and reported to the Hungarian 
Scientific and Medical Research Council Ethics Committee and the local ethics committees. If 
any SAEs occur, the trial will be interrupted and an investigation will be performed. 
 
Duration of the trial 
The annual number of laparoscopic gynaecological surgery is around 1500 in the participating 
study centres. Recruitment of the participants is expected within 24 months. Final data 
collection and estimated completion date of the trial is 31 October, 2027. 
 
 
 
 
 
 
 
 
 
 

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This is the latest version of the study protocol. 
 
Date: 08/09/2025