Diagnostic Performance of a Net Ultrafiltration Challenge to Predict Preload Dependence in Critically Ill Patients Under Continuous Renal Replacement Therapy
Phase: NA
Conditions: Acute Kidney Injury
Sponsor: Hospices Civils de Lyon

Diagnostic performance of a rapid ultrafiltration test to 
assess preload dependence in critically ill patients treated 
with continuous renal replacement therapy. 
 
UF CHALLENGE Study 
 
 
 
 
This is a translation from the original French document. 
In case of discrepancy, the original French version shall prevail. 
 
The 
publication 
of 
results 
related 
to 
this 
protocol 
can 
be 
find 
at: 
https://ccforum.biomedcentral.com/articles/10.1186/s13054-025-05674-3 (Biscarrat et 
al. 2025 Critical Care) 
 
 
 
Sponsor 
Hospices Civils de Lyon 
BP 22513  
Quai des Célestins 
69229 LYON Cedex 02 
 
Principal Investigator 
Dr. Laurent Bitker 
Intensive Care Medicine – Critical Care Unit 
Hôpital de la Croix Rousse, GHN 
103 Grande Rue de la Croix Rousse 
69004 Lyon 
Email: laurent.bitker@chu-lyon.fr 
Tel: +33 (0)4 26 10 94 93 
 
Protocol Version 
Version 02 – March 16, 2022 
 
 

SUMMARY 
Background / Rationale 
A positive fluid balance is a risk factor associated with increased mortality in intensive 
care (Vaara et al. 2012, Critical Care). Continuous renal replacement therapy (CRRT) 
is an effective means of regulating fluid overload in patients with acute kidney injury in 
critical care settings. However, this organ support technique may induce episodes of 
hemodynamic instability. Such episodes often lead to discontinuation of fluid removal 
during CRRT, although these events are not necessarily associated with cardiac 
preload dependence (Bitker et al. 2016, Crit Care; Chazot et al. 2021, Crit Care). 
Therefore, the causal link with ultrafiltration is not always certain, and fluid removal 
could potentially be continued. 
 
Currently, the best means of identifying a preload-dependent hemodynamic profile is 
a postural maneuver (passive leg raise or Trendelenburg), which is a validated test for 
assessing the impact of insufficient venous return on cardiac output (Monnet et al. 2016 
Intensive Care; Yonis et al. 2017 Crit Care Med). However, these maneuvers only 
identify patients who are already preload-dependent. To date, no clinical test is 
available to identify patients at risk of becoming preload-dependent and thus suffering 
the deleterious consequences of inappropriate fluid removal. 
We aim to evaluate a novel predictive test based on a rapid ultrafiltration challenge, 
which could reveal a patient’s transition into preload dependence. Validation of this test 
would allow adjustment of net ultrafiltration (fluid removal) according to the 
hemodynamic response in terms of cardiac preload. 
 
Primary Objective 
To assess the diagnostic performance of a rapid ultrafiltration test (without 
distinguishing between 15- and 30-minute trials) in detecting preload dependence in 
critically ill patients treated with continuous renal replacement therapy, by quantifying 
the change in cardiac index induced by the test and comparing it to that induced by a 
postural maneuver (reference standard) performed after the ultrafiltration test. 
 
Secondary Objectives 
• 
To assess the diagnostic performance of the 15-minute and 30-minute rapid 
ultrafiltration tests, respectively, using the same methodology. 
• 
To determine the optimal threshold of cardiac index variation that defines 
preload dependence for each test (pooled and separately), with calculation of 
sensitivity, specificity, positive and negative predictive values. 
• 
To compare the diagnostic performance of ultrafiltration tests (pooled and 
separate) with that of the pre-test postural maneuver. 
• 
To compare the diagnostic performance between the 15-minute and 30-minute 
tests. 
• 
To evaluate the impact of ultrafiltration tests on additional hemodynamic 
variables (absolute values and relative changes from baseline): central venous 
pressure, heart rate, mean and pulse arterial pressure, extravascular lung 

water, pulmonary vascular permeability index, and global end-diastolic volume 
index. 
• 
To assess the ability of ultrafiltration tests (pooled and separate) to predict 
hemodynamic instability with preload dependence occurring within 8 hours 
following the test. 
 
Methodology / Study Design 
• 
Pilot study 
• 
Physiological, prospective, single-center, open-label 
• 
Sequential 
crossover 
design 
with 
sealed-envelope 
randomization 
of 
intervention order 
• 
Diagnostic test evaluation (rapid ultrafiltration challenge) 
 
Primary Endpoint 
Diagnostic performance of a rapid ultrafiltration test (regardless of duration), assessed 
by the area under the ROC curve (receiver operating characteristics) of cardiac index 
variation compared to the reference measurement (postural maneuver performed after 
the test). 
 
Secondary Endpoints 
• 
Diagnostic performance of the 15-minute and 30-minute rapid ultrafiltration 
tests, assessed by ROC analysis of cardiac index variation and comparison with 
the reference maneuver. 
• 
Optimal thresholds (and 95% CI) of cardiac index variation for each test, 
determined using the Youden index, with associated sensitivity, specificity, PPV, 
and NPV. 
• 
Comparative diagnostic performance of ultrafiltration tests (pooled and 
separate) versus pre-test postural maneuver, and between tests (15 vs. 30 
minutes). 
• 
ROC AUC values compared using DeLong’s method. 
• 
Hemodynamic variables measured by cardiac output monitoring (CVP, HR, 
MAP, pulse pressure, EVLW, PVPI, GEDVi), analyzed as absolute values and 
changes from baseline, correlated with cardiac index variation. 
• 
Incidence of hemodynamic instability (tachycardia, hypotension, decreased 
cardiac index, mottling) within 8 hours after the ultrafiltration test. 
 
Target Population 
Adult ICU patients (under mechanical ventilation and sedation) with acute kidney injury 
(KDIGO stage 3) requiring continuous renal replacement therapy initiated within the 
past 14 days. 
 
Sample Size 
N = 20 evaluable patients, each undergoing 2 tests → total of 40 rapid ultrafiltration 
challenges. 

 
Study Duration 
• 
Inclusion period: 18 months 
• 
Maximum participation per patient: 72 hours 
• 
Total study duration: 18 months + 3 days 
 
Expected Outcomes 
The current reference dynamic test (passive leg raise or Trendelenburg) remains 
imperfect in assessing tolerance to fluid removal during CRRT, with sensitivity <80%. 
The UF challenge may prove more sensitive, particularly in patients at the borderline 
between the ascending and plateau phases of the Frank-Starling curve. This simple, 
dynamic, low-cost test could help clinicians individualize ultrafiltration prescriptions, 
avoid deleterious hypotension, and rapidly integrate into clinical practice. Currently, no 
specific dynamic test exists to evaluate the safety and efficacy of fluid removal in this 
population. 
 
 
 

GENERAL INFORMATION 
 
Title: Diagnostic performance of a rapid ultrafiltration test to assess preload 
dependence in critically ill patients treated with continuous renal replacement therapy. 
 
Project Identifiers and Update History 
• 
Sponsor Code: 69HCL21_1250 
• 
ClinicalTrials.gov registration number: NCT05214729 
• 
CPP Sud-Est VI favorable opinion date: XX/XX/XXXX 
 
Version History 
Version Date 
Reason for Update 
1 
02/11/2021 Initial draft 
2 
16/03/2022 Comments from CPP 
 
Sponsor 
Identity: Hospices Civils de Lyon 
BP 22513  
Quai des Célestins69229 LYON Cedex 02 
Signature of the protocol on behalf of the Sponsor: 
Alexandre PACHOT, Director of Health Research 
Hospices Civils de Lyon, Health Research Directorate, 
Administrative Headquarters,  
BP 2251,  
3 Quai des Célestins,  
69229 LYON Cedex 02 
Tel: +33 (0)4 72 40 68 52 
 
Research Manager at Sponsor Level: Thierry HEREMBERT 
Hospices Civils de Lyon, Health Research Directorate, 
Administrative Headquarters,  
BP 2251,  
3 Quai des Célestins,  
69229 LYON Cedex 02 
Tel: +33 (0)4 72 40 70 87 
 
Regulatory Affairs Manager: Valérie PLATTNER 
Hospices Civils de Lyon, Health Research Directorate, 
Administrative Headquarters,  
BP 2251,  
3 Quai des Célestins,  
69229 LYON Cedex 02 
Tel: +33 (0)4 72 40 68 40 

 
Investigators 
Principal Investigator: Dr. Laurent Bitker 
Intensive Care Medicine – Critical Care Unit 
Hôpital de la Croix Rousse, GHN 
103, Grande Rue de la Croix Rousse 
69004 Lyon 
Email: laurent.bitker@chu-lyon.fr 
Tel: +33 (0)4 26 10 94 93 
 
Associated Investigator: Prof. Jean-Christophe Richard 
Intensive Care Medicine – Critical Care Unit 
Hôpital de la Croix Rousse, GHN 
103, Grande Rue de la Croix Rousse 
69004 Lyon 
Email: j-christophe.richard@chu-lyon.fr 
Tel: +33 (0)4 26 10 94 93 
 
Associated Scientist: Ms. Charlotte Biscarrat (Resident) 
Intensive Care Medicine – Critical Care Unit 
Hôpital de la Croix Rousse, GHN 
103, Grande Rue de la Croix Rousse 
69004 Lyon 
Email: charlotte.biscarrat@chu-lyon.fr 
Tel: +33 (0)4 26 10 94 93 
 
SCIENTIFIC JUSTIFICATION 
Current State of Knowledge – Rationale 
A positive fluid balance has been shown to be an independent risk factor for mortality 
in intensive care, particularly in patients with septic shock, ARDS, and acute kidney 
injury. Fluid overload can impair the function of several organs, including the kidneys. 
Ultrafiltration contributes to controlling fluid balance. Compared to liberal fluid 
strategies, conservative strategies including ultrafiltration during dialysis may 
accelerate extubation in ARDS patients. 
 
The main risk of excessive fluid removal is hemodynamic instability. Intra-dialytic 
hypotension is deleterious and may impair renal recovery. Hypotension during dialysis 
often leads to interruption of ultrafiltration, negatively impacting fluid balance control. A 
high ultrafiltration rate is associated with increased mortality, although no universal 
threshold exists. 
 
Excessive depletion may reduce cardiac output when patients are preload-dependent 
(on the ascending portion of the Frank-Starling curve). However, not all hypotensive 
episodes are preload-dependent; some relate to vasoplegia or myocardial dysfunction. 

Currently, the most reliable tool for diagnosing preload dependence is a dynamic test: 
passive leg raise (supine) or Trendelenburg (prone) with continuous cardiac output 
monitoring. A ≥10% increase in cardiac output indicates preload dependence. Studies, 
including work by our team, confirm sensitivity and specificity >85%. This test performs 
well to identify patient who are preload-dependent, and who are consequently at higher 
risk of preload-dependent hypotension. Yet, in preload-independent patients (i.e. those 
with a negative passive leg raising test, no validated predictive test exists for 
ultrafiltration-related hypotension in relation with their switch to a preload-dependent 
status. 
 
Research Hypothesis 
A 250 mL rapid ultrafiltration challenge (15 or 30 minutes) may help identify preload-
independent patients at risk of becoming preload dependent during CRRT 
 
Justification of Methodological Choices 
• 
Sequential crossover design: each patient serves as their own control, limiting 
variability. 
• 
Randomization of challenge order prevents bias. 
• 
250 mL volume chosen as it mimics passive leg raise (~300 mL). 
• 
Two rates (15 vs. 30 minutes) tested to assess the effect of ultrafiltration kinetics 
and plasma refilling. 
 
The PiCCO® Monitoring Device 
The device combines transpulmonary thermodilution and pulse contour analysis for 
continuous cardiac output and displays advanced hemodynamic parameters 
(extravascular lung water, pulmonary vascular permeability index, global end-diastolic 
volume index). 
 
Benefit/Risk Assessment 
• 
Benefit: collective, through validation of a new predictive test. 
• 
Risk: minimal, transient hemodynamic instability possible 
• 
No additional invasive procedures required. 
 
Expected Outcomes 
A UF challenge may have higher diagnostic performance than the passive leg raising 
test to identify patients at the transition between preload independence and 
dependence. It is simple, dynamic, inexpensive, and potentially useful in guiding 
ultrafiltration in CRRT patients. 
 
 
 

RESEARCH OBJECTIVES 
Primary Objective 
To evaluate the diagnostic performance of a rapid ultrafiltration challenge (250 mL over 
15 or 30 minutes) in detecting preload dependence in preload independent critically ill 
patients treated with continuous renal replacement therapy. 
 
Diagnostic accuracy will be assessed by the change in calibrated cardiac index 
induced by the ultrafiltration challenge compared with the reference postural maneuver 
(passive leg raise or Trendelenburg) performed after the challenge. 
 
Secondary Objectives 
1. To evaluate separately the diagnostic performance of the 15-minute and 30-
minute UF challenges. 
2. To determine the optimal threshold of calibrated cardiac index variation defining 
preload dependence for each test (pooled and separate), with sensitivity, 
specificity, PPV, and NPV. 
3. To compare diagnostic performance of UF challenges (pooled and separate) 
with that of the pre-test postural maneuver. 
4. To compare diagnostic performance between the 15-minute and the 30-minute 
challenges. 
5. To assess the effect of ultrafiltration challenges on other hemodynamic 
parameters (absolute values and relative changes from baseline): central 
venous pressure (CVP), heart rate (HR), mean arterial pressure (MAP), pulse 
pressure, extravascular lung water (EVLW), pulmonary vascular permeability 
index (PVPI) and global end-diastolic volume index (GEDVi) 
6. To evaluate the ability of ultrafiltration challenges to predict hemodynamic 
instability with preload dependence within 8 hours after the test. 
 
STUDY DESIGN / METHODOLOGY 
Type of Research 
• 
Pilot study 
• 
Physiological, prospective, single-center, open-label 
• 
Sequential crossover design with randomization of challenges’ order 
• 
Diagnostic test evaluation 
 
Study Population 
Inclusion Criteria 
• 
Adults ≥18 years hospitalized in the ICU 
• 
Mechanical ventilation and sedation 
• 
Acute kidney injury KDIGO stage 3 
• 
CRRT initiated <14 days before inclusion 
• 
With a calibrated continuous cardiac index monitoring device in place (PiCCO®, 
Pulsion Medical, Feldkirch, Germany)  

• 
Informed consent (patient or representative) 
 
Exclusion Criteria 
• 
Arterial lactate > 4 mmol/L 
• 
Calibrated cardiac index < 2 or > 4 L/min/m2 
• 
Preload dependence identified within the preceding 2 hours 
• 
ECMO 
• 
Acute hemorrhage 
• 
End stage chronic kidney disease or renal graft recipient 
• 
Acute stroke with coma 
• 
Fulminant hepatitis 
• 
Inability to perform PLR: amputation, inferior vena cava obstruction, abdominal 
compartment syndrome 
• 
Pregnancy or breastfeeding 
• 
Imminent death 
• 
Decision of withholding of care 
• 
Patients under legal protection (guardianship, trusteeship, detention) 
• 
Already included in the study 
 
Number of Patients 
• 
20 patients included 
• 
Each patient undergoes 2 ultrafiltration challenges (15- and 30-minute, in 
randomized order) 
• 
Total: 40 evaluable challenges 
 
Randomization 
• 
Randomized order determined by sealed envelope method 
• 
Each patient serves as their own control 
 
Blinding 
• Not feasible given the study design 
 
Co-interventions 
Recommendation for not changing any of the following parameters, prescription or 
settings during the trial’s interventions: 
• Sedation 
• Mechanical ventilation 
• Vasopressor and inotrope support 
• Fluid bolus therapy or transfusion 
 
Study Procedures 
1. Baseline data collection (demographics, clinical scores, renal data, 
hemodynamics) 

2. Calibration of the monitoring device and pre-test postural maneuver (PLR or 
Trendelenburg) during 1 minute with collection of the relative change in 
continuous cardiac index 
3. Ultrafiltration challenge: 250 mL over 15 or 30 minutes (randomized), by setting 
a UF flow of 1000 ml/h or 500 ml/h, respectively 
4. Re-calibration of the monitoring device and post-test postural maneuver 
(reference standard, PLR or Trendelenburg) during 1 minute with collection of 
the relative change in continuous cardiac index 
5. Repeat sequence for second challenge after a wash-out period of 24h (cross-
over design) 
6. Follow-up: monitoring for 8 hours post-test for instability 
 
Data Collected 
• 
Demographics: age, sex, weight, height 
• 
Clinical: history, reason for ICU admission, severity scores (SAPS II, SOFA) 
• 
Renal: CRRT indication and parameters 
• 
Hemodynamics: CI, CVP, HR, MAP, PP, EVLW, PVPI, GEDVi (before/after each 
step), vasopressor dosage 
• 
Ventilatory settings: VT, PEEP, FiO2, arterial blood gas results 
• 
Results of the pre and post-test postural maneuvers 
• 
Any severe and non-severe adverse events 
 
ENDPOINTS / EVALUATION CRITERIA 
Primary Endpoint 
The diagnostic performance of the rapid ultrafiltration challenge (pooled 15- and 30-
minute tests). 
• 
Performance assessed by the area under the ROC curve (AUC) of cardiac index 
variation. 
• 
Reference: continuous cardiac index relative variation induced by the post-test 
postural maneuver performed after the challenge. 
 
Secondary Endpoints 
1. Respective diagnostic performance of the 15-minute and 30-minute challenges 
(ROC AUC). 
2. Determination of the optimal threshold of cardiac index variation (Youden index) 
with sensitivity, specificity, PPV, and NPV. 
3. Comparative performance of challenges (pooled and separate) versus the pre-
test postural maneuver. 
4. Comparison of diagnostic performance between the 15-minute and 30-minute 
challenges ROC AUCs compared using DeLong’s test. 
5. Analysis of additional hemodynamic parameters: CVP, HR, MAP, Pulse 
pressure, EVLW, PVPI and GEDVi (absolute values and relative changes, 
correlated with cardiac index variation). 

6. Incidence of hemodynamic instability within 8 hours post-test (tachycardia, 
hypotension, decreased CI, mottling). 
 
Study duration 
• 
Inclusion period: 18 months 
• 
Maximum participation per patient: 72 hours 
• 
Total study duration: 18 months + 3 days 
 
Sample size 
• 
20 patients planned. 
• 
Each undergoes 2 ultrafiltration challenges (15- and 30-minute, randomized). 
• 
Total: 40 evaluable ultrafiltration challenges. 
The sample size was chosen pragmatically, consistent with the pilot/exploratory nature 
of the study. 
 
STUDY PROCEDURES AND CONDUCT 
Overall Study Flow 
1. Screening and Inclusion 
o Verify inclusion and exclusion criteria. 
o Provide information to patient or legally authorized representative; obtain 
consent in compliance with French law. 
2. Baseline Assessment 
o Collect demographics and clinical data (age, sex, weight, height, SAPS 
II, SOFA, reason for ICU admission, history). 
o Record renal data (CRRT indication and parameters, time since CRRT 
initiation). 
o Baseline hemodynamic measurements: CI, CVP, HR, MAP, PP, EVLW, 
PVPI, GEDVi, vasopressor dosage 
o Mechanical ventilation settings 
3. Randomization 
o Determine challenge sequence (15 vs 30 minutes) using sealed 
envelopes. 
4. Pre-test postural maneuver 
o Passive leg raise (supine) or Trendelenburg (prone). 
o Record hemodynamic parameters before and during maneuver. 
5. Ultrafiltration Challenge 
o Remove 250 mL with UF over 15 or 30 minutes. 
o Monitor CI and hemodynamic parameters continuously. 
o Record parameters at the end of challenge. 
6. Post-test Postural Maneuver (Reference) 
o Repeat maneuver (PLR or Trendelenburg). 
o Record hemodynamic parameters before and during maneuver. 
7. Follow-up 
o Any hemodynamic instability episodes occurring over the following 8h 

8. Second Ultrafiltration Challenge 
o After a 24h wash-out period, repeat procedure with the alternate duration 
(30 or 15 minutes). 
o Same sequence: pre-test maneuver → challenge → post-test maneuver. 
9. Follow-up 
o Monitor for 8 hours post-challenges. 
o Record any hemodynamic instability. 
 
Data Management 
• 
Data recorded in a secure electronic case report form (eCRF). 
• 
Source documents: ICU medical files, CRRT charts, PiCCO® data, nursing 
observation sheets. 
• 
Data entry performed by investigators, validated and monitored by sponsor. 
 
Safety Monitoring 
• 
Continuous monitoring of cardiac output and hemodynamics during challenges. 
• 
Adverse events (AEs) and serious adverse events (SAEs) recorded and 
reported. 
• 
Risks: transient hypotension or tachycardia, reversible and clinically 
manageable. 
 
Premature Discontinuation 
Patients may be withdrawn if: 
• 
Consent withdrawn. 
• 
Serious adverse event occurs. 
• 
Investigator deems it in patient’s best interest. 
• 
Limitation of therapeutic effort decided. 
• 
Technical impossibility (e.g., PiCCO® failure, CRRT interruption). 
 
SAFETY EVALUATION AND RISK MANAGEMENT 
Potential Risks for Participants 
• 
The ultrafiltration challenge consists of removing 250 mL of ultrafiltrate over 15 
or 30 minutes. 
• 
Main anticipated risk: transient hemodynamic instability, such as hypotension, 
tachycardia, decreased cardiac index, or mottling. 
• 
These events are expected to be limited, reversible, and continuously monitored 
with PiCCO® cardiac output monitoring. 
• 
No additional invasive procedure is required beyond standard ICU monitoring. 
 
Adverse Events (AEs) and Serious Adverse Events (SAEs) 
• 
Adverse Event (AE): any unfavorable or unintended medical occurrence during 
research, whether or not related to the investigational procedure. 

• 
Serious Adverse Event (SAE): an event that results in death, is life-threatening, 
requires or prolongs hospitalization, results in significant disability, or is deemed 
medically significant by the investigator. 
 
Collection and Reporting 
• 
All AEs and SAEs occurring from the start of ultrafiltration challenges until 8 
hours post-procedure will be documented in the eCRF. 
• 
The investigator will assess causality (related or not to the ultrafiltration 
challenge). 
• 
SAEs must be reported to the sponsor within 24 hours of investigator 
awareness. 
• 
The sponsor will notify relevant authorities (CPP, ANSM if applicable) in 
compliance with French regulations. 
 
Measures for Participant Safety 
• 
Continuous monitoring ensures early detection of instability. 
• 
If instability occurs (e.g., MAP <60 mmHg, sustained tachycardia, cardiac index 
decrease >20%), the ultrafiltration challenge will be immediately stopped, and 
corrective treatment administered (fluids, vasopressors, etc.). 
• 
The investigator may withdraw the patient from the study in case of 
unacceptable risk. 
 
STATISTICAL ANALYSIS 
General Principles 
• 
Analyses performed using R software (latest version available). 
• 
Two-sided significance level set at 0.05. 
• 
95% confidence intervals reported. 
• 
Analyses conducted on the intention-to-treat and per-protocol population 
(patients with at least one evaluable ultrafiltration challenge). 
 
Primary Analysis 
• 
The primary endpoint is the diagnostic performance of the ultrafiltration 
challenge (15- and 30-minute tests pooled). 
• 
Performance assessed by calculating the area under the ROC curve (AUC) of 
cardiac index variation compared with the post-test postural maneuver. 
• 
AUC values will be reported with 95% confidence intervals. 
 
Secondary Analyses 
1. Diagnostic performance of the 15-minute and 30-minute ultrafiltration challenge 
alone (ROC AUC). 
2. Determination of the optimal threshold of cardiac index variation (Youden index) 
defining preload dependence, with sensitivity, specificity, PPV, and NPV. 
3. Comparative diagnostic performance of ultrafiltration challenges (pooled and 
separate) versus the pre-test postural maneuver, compared using the 

respective ROC AUCs of 15-minute and 30-minute challenges using DeLong’s 
test. 
4. Analysis of additional hemodynamic parameters (CVP, HR, MAP, PP, EVLW, 
PVPI, GEDVi) in absolute values and relative changes from baseline, correlated 
with cardiac index variation using Pearson or Spearman correlation. 
5. Description of the incidence of hemodynamic instability within 8 hours post-test, 
expressed as proportions with 95% confidence intervals. 
 
Handling of Missing Data 
• 
Missing data will not be imputed. 
• 
Analyses will be based on available data. 
• 
The extent and reasons for missing data will be described. 
 
Interim Analysis 
No interim analysis is planned. 
 
QUALITY ASSURANCE, ETHICS, AND DATA MANAGEMENT 
Regulatory and Ethical Aspects 
• 
The study will be conducted in compliance with the Declaration of Helsinki (2013 
version) and the principles of Good Clinical Practice (ICH E6 R2). 
• 
The protocol, patient information, and consent form have been submitted to and 
approved by the CPP Sud-Est VI (Comité de Protection des Personnes). 
• 
The study has been declared to the CNIL (Commission Nationale de 
l’Informatique et des Libertés) in accordance with French law and the General 
Data Protection Regulation (GDPR, EU 2016/679). 
• 
Any substantial protocol amendments will be submitted for approval to the CPP 
and, if necessary, to the French National Agency for Medicines and Health 
Products Safety (ANSM). 
 
Informed Consent 
• 
Informed consent must be obtained from each participant or their legally 
authorized representative before any research-specific procedure. 
• 
If the patient regains decision-making capacity, consent will be sought again for 
continuation. 
• 
Consent procedures comply with the French Jardé Law for research involving 
human subjects. 
 
Confidentiality and Data Protection 
• 
Participant data will be coded with a unique study identifier. 
• 
Only authorized members of the research team and sponsor will access 
identifiable data. 
• 
Data will be securely stored in a password-protected electronic case report form 
(eCRF). 

• 
In compliance with GDPR and French law, participants may access, rectify, or 
delete their data by contacting the sponsor. 
 
Monitoring and Quality Assurance 
• 
The sponsor’s Clinical Research Unit (Hospices Civils de Lyon) will conduct 
monitoring visits to ensure compliance with the protocol and regulatory 
requirements. 
• 
Source data verification will be performed to ensure consistency between 
medical records and eCRF entries. 
• 
Monitoring activities will be documented in formal monitoring reports. 
 
Archiving 
• 
Essential study documents (protocol, CRFs, monitoring reports, patient files, 
consent forms) will be archived for 15 years after study completion. 
• 
Electronic data will also be securely stored by the sponsor for the same duration. 
 
Insurance 
• 
The sponsor has subscribed to an insurance policy covering the civil liability of 
investigators and institutions involved, in accordance with Article L.1121-10 of 
the French Public Health Code. 
 
Publication and Communication of Results 
• 
Results will be submitted for publication in a peer-reviewed international 
scientific journal. 
• 
Authorship will follow the criteria defined by the International Committee of 
Medical Journal Editors (ICMJE). 
• 
Negative or inconclusive results will also be published. 
• 
Results may be presented at national and international scientific meetings. 
 
REFERENCES 
1. Vaara ST, et al. Fluid overload is associated with increased mortality in critically 
ill patients with acute kidney injury. Crit Care. 2012;16:R197. 
2. Wiedemann HP, et al. Comparison of two fluid-management strategies in acute 
lung injury. N Engl J Med. 2006;354(24):2564-2575. 
3. Payen D, et al. A positive fluid balance is associated with a worse outcome in 
patients with acute renal failure. Crit Care. 2008;12(3):R74. 
4. Prowle JR, et al. Fluid overload and acute kidney injury. Nat Rev Nephrol. 
2010;6(12):641-649. 
5. National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. 
Comparison of conservative vs. liberal fluid management strategy in ARDS. N 
Engl J Med. 2006;354:2564-2575. 
6. Flythe JE, et al. Intradialytic hypotension: clinical outcomes and management 
approaches. Semin Dial. 2017;30(6):473-481. 

7. Bitker L, et al. Hemodynamic response to fluid challenge during renal 
replacement therapy. Crit Care. 2016;20:303. 
8. Chazot C, et al. Hemodynamic effects of ultrafiltration during CRRT. Crit Care. 
2021;25:14. 
9. Monnet X, et al. Passive leg raising for predicting fluid responsiveness: a 
systematic review and meta-analysis. Intensive Care Med. 2016;42:1935–1947. 
10. Yonis H, et al. Trendelenburg maneuver to assess fluid responsiveness in prone 
patients with ARDS. Crit Care Med. 2017;45(11):e1111-e1117. 
11. Bitker L, et al. Passive leg raise test predicts intradialytic hypotension in ICU 
patients. Crit Care. 2016;20:303. 
12. Preau S, et al. Predictive value of IVC diameter variations for fluid 
responsiveness in mechanically ventilated patients. Crit Care Med. 
2010;38:1462–1467.