Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| 2025-520744-14-00 | EU Trial (CTIS) Number |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| Ziekenhuis aan de Stroom | OTHER |
| Research Foundation Flanders | OTHER |
Not provided
Not provided
Not provided
This study is enrolling adult patients who require a prolonged stay in the intensive care unit (ICU). These patients often receive large amounts of intravenous fluids, which can contain more salt (sodium and chloride) than the body normally needs. Extra salt and water can build up in the body and may delay recovery.
The study will test two strategies:
Fluid creep: These are fluids used to dilute medications or keep intravenous lines open. Usually, the choice is based on habit. In the intervention group, a salt-free glucose 5% solution will be used (if the responsible pharmacist confirms it is compatible with the medication).
Maintenance fluids: These fluids cover daily needs for water and electrolytes. In the intervention group, a lower-salt solution (NaCl 0.3% in glucose 3.3%) will be given, with volume decided by the treating physician.
The comparison group will receive usual care: NaCl 0.9% (commonly called "normal saline") for fluid creep, and an isotonic solution (PlasmaLyte) for maintenance fluids.
The main outcome is the number of days patients are alive and free of life support (such as ventilator or dialysis) during the first 90 days. Other outcomes include abnormal sodium, chloride, or glucose levels, fluid balance and need for diuretics, kidney injury, use of dialysis, time on the ventilator, survival, and length of ICU and hospital stay.
A smaller substudy (SALADIN) will measure in detail how the body handles sodium, chloride, and water using additional calculation on blood tests, urine collections, body weight, and bioimpedance analysis
Critically ill patients admitted to the intensive care unit (ICU) often receive large volumes of intravenous fluids. Beyond resuscitation fluids, which have been extensively studied, two other sources contribute substantially to fluid, sodium, and chloride exposure:
Fluid creep, the use of diluents and small-volume infusions to dissolve medications or maintain line patency.
Maintenance fluids, prescribed to cover daily fluid and electrolyte needs when oral intake is insufficient.
Together, fluid creep and maintenance fluids account for more than half of all intravenous fluids given in ICU patients. These fluids frequently contain supraphysiologic amounts of sodium and chloride. Because the kidneys of critically ill patients are unable to excrete these excesses efficiently, sodium and chloride accumulate, leading to positive fluid balances, electrolyte disturbances, pulmonary edema, renal dysfunction, and prolonged organ support. Observational data have linked both fluid overload and hyperchloremia to higher morbidity and mortality.
Prior research has focused mainly on resuscitation fluids. Large randomized trials comparing chloride-rich saline to balanced crystalloids demonstrated only small differences in outcomes, in part because resuscitation fluids make up a limited fraction of overall fluid exposure. In contrast, fluid creep and maintenance solutions offer a larger and modifiable source of sodium and chloride. Small studies and volunteer experiments have shown that sodium-poor maintenance fluids and sodium-free diluents reduce fluid retention and hyperchloremia, but their effect on patient-centered outcomes has never been tested in a large randomized trial.
CRUSADERS (CReep and maintenance flUid Sodium chloride ADministration Reduction in cRitically ill adultS) is a multicenter, randomized, double-blind, phase IV, low-intervention trial designed to address this evidence gap. The trial compares two strategies:
NaCl-poor arm (intervention):
Fluid creep: medications are dissolved in glucose 5% (except when another diluent is mandatory); line patency fluids are glucose 5%.
Maintenance fluids: NaCl 0.3% in glucose 3.3%, with volume determined by the treating physician.
NaCl-rich arm (control):
Fluid creep: medications are dissolved in NaCl 0.9%; line patency fluids are NaCl 0.9%.
Maintenance fluids: PlasmaLyte, with volume determined by the treating physician.
All study fluids are licensed, widely used hospital products. Blinding is achieved through repackaging into opaque study bags labeled only with trial codes. Treating teams decide indications and volumes, ensuring pragmatic applicability while isolating the effect of fluid composition.
The primary endpoint is days alive and without life support (DAWOLS) at 90 days after ICU admission, an outcome that integrates survival and duration of mechanical ventilation or renal replacement therapy. Secondary outcomes include electrolyte disorders (hyponatremia, hypernatremia, hyperchloremia), fluid balance and diuretic use, acute kidney injury, renal replacement therapy, mechanical ventilation, glycemic control, mortality, and ICU/hospital length of stay. Exploratory outcomes include biochemical markers of salt-induced catabolism such as the serum urea-to-creatinine ratio.
A nested substudy (SALADIN - SAlt baLAnce Detailed INsight) will provide mechanistic insights into sodium, chloride, and water handling. In this subgroup, detailed daily balances will be calculated from fluid intake and 24-hour urine collections, combined with measurements of free water clearance, bioelectrical impedance analysis, body weight, and volume kinetics modeling.
The trial will recruit 640 adult ICU patients across four Belgian mixed ICUs. Inclusion requires expected ICU stay >48 hours and anticipated exposure to maintenance fluids or significant fluid creep. Patients with contraindications to hypotonic fluids, severe baseline hyponatremia, imminent death, chronic dialysis, or exclusive palliative/organ donation admission are excluded.
Patients are randomized 1:1 with stratification by site, mechanical ventilation, and surgical admission. Study treatment continues throughout the ICU stay or until study fluids are no longer available according to the blinded allocation schedule (minimum 28 days after randomization). Follow-up continues until 90 days after ICU admission.
The CRUSADERS trial is investigator-initiated, funded by the Research Foundation Flanders (FWO), and sponsored by Antwerp University Hospital. It is conducted under European Union (EU) Clinical Trial Regulation (536/2014) with central review via the Clinical Trial Information System (CTIS). Given the exclusive use of approved fluids in routine indications, the trial is classified as low-intervention. A Data and Safety Monitoring Board oversees safety with predefined stopping rules and interim analysis after half the planned population has been followed.
By targeting sodium and chloride in fluid creep and maintenance solutions rather than resuscitation fluids, CRUSADERS aims to test a simple, cost-neutral, and widely applicable strategy to improve survival and reduce life support dependence in critically ill patients. If positive, the trial may provide a strong evidence base for revising international fluid therapy guidelines and daily ICU practice.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sodium chloride reduction strategy, the NaCl-poor arm | Active Comparator | Participants receive a sodium-chloride reduction strategy during their ICU stay. Medications are diluted in glucose 5% (unless another solvent is mandatory), and intravenous line patency fluids are glucose 5%. Daily maintenance fluids are NaCl 0.3% in glucose 3.3%, with the volume determined by the treating physician. The goal is to reduce sodium and chloride exposure while maintaining fluid and electrolyte support. Interventions: Drug: Glucose 5% Drug: NaCl 0.3% in Glucose 3.3% |
|
| Isotonic fluid strategy, the NaCl-rich arm | Active Comparator | Participants receive a standard isotonic fluid strategy during their ICU stay. Medications are diluted in NaCl 0.9% (unless another solvent is mandatory), and intravenous line patency fluids are NaCl 0.9%. Daily maintenance fluids are PlasmaLyte, with the volume determined by the treating physician. This reflects the common standard of care in many ICUs. Interventions: Drug: NaCl 0.9% Drug: PlasmaLyte |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Glucose 5% for fluid creep | Drug |
|
| Measure | Description | Time Frame |
|---|---|---|
| Days alive and without life support at day 90 (DAWOLS90) | The composite endpoint DAWOLS90 is defined as the number of days alive and without the use of life support within 90 days counted from ICU admission. Unit of measure: days. Patients who die before D90 are assigned zero days. The following life-support therapies are considered 1/ Mechanical ventilation: includes invasive and noninvasive ventilation, including continuous positive airway pressure (CPAP) but excluding high-flow nasal oxygen. Each ICU day counts as a ventilator day if support is in place. Post-extubation days are counted as ventilator-free only if no re-intubation occurs within 48 hours. 2/ Renal replacement therapy (RRT): includes continuous RRT, peritoneal dialysis, or intermittent hemodialysis (IHD). If IHD is given, periods with up to 3 days between sessions are counted as days with RRT. | From admission until day 90 counted from ICU admission (= Day 1) |
| Measure | Description | Time Frame |
|---|---|---|
| Occurrence of moderate and severe hyponatremia | Defined as the number of participants with at least one episode of: Moderate hyponatremia: serum sodium 125-129 mmol/L Severe hyponatremia: serum sodium <125 mmol/L To be counted as an event, the sodium level must decrease by at least 3 mmol/L from baseline to reduce misclassification due to pre-existing mild hyponatremia or analytical variation. Assessments are based on daily routine morning serum sodium values from the central laboratory (ion-specific electrode). If available, paired serum albumin and point-of-care sodium values (measured within 2 hours) will be recorded to allow cross-checks and sensitivity analyses |
| Measure | Description | Time Frame |
|---|---|---|
| Daily sodium, chloride and glucose administration | Total daily amount of sodium, chloride, and glucose (mmol or g per ICU day) from study fluids, non-study maintenance, replacement and resuscitation fluids, enteral and parenteral nutrition, and blood products (sodium/chloride content estimated from reference values). Excludes non-study fluid creep and oral intake. | From ICU admission until ICU discharge (up to day 90 counted from ICU admission). |
Inclusion criteria
Exclusion Criteria:
Additional exclusion criteria for the SALADIN nested substudy
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Petra Y Vertongen | Contact | +3238214404 | petra.vertongen@uza.be | |
| Leen Ameryckx | Contact | +3232757005 | leen.ameryckx@uza.be |
| Name | Affiliation | Role |
|---|---|---|
| Niels Van Regenmortel, MD, PhD | Ziekenhuis aan de Stroom (ZAS) Network of Hospitals | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| ZAS Middelheim | Not yet recruiting | Antwerp | 2020 | Belgium | ||
| ZAS Cadix |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36915265 | Background | Granholm A, Schjorring OL, Jensen AKG, Kaas-Hansen BS, Munch MW, Klitgaard TL, Crescioli E, Kjaer MN, Strom T, Lange T, Perner A, Rasmussen BS, Moller MH. Association between days alive without life support/out of hospital and health-related quality of life. Acta Anaesthesiol Scand. 2023 Jul;67(6):762-771. doi: 10.1111/aas.14231. Epub 2023 Mar 21. | |
| 29589054 |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 25, 2025 | Sep 7, 2025 |
Not provided
This is an investigator-initiated, multicenter, randomized, double-blind, parallel-group phase IV trial conducted in four mixed ICUs in Belgium. Adult patients expected to require prolonged ICU care are randomized 1:1 to a sodium-chloride reduction strategy (NaCl-poor arm) or to a standard isotonic fluid strategy (NaCl-rich arm). Randomization is stratified by study site, surgical admission, and invasive mechanical ventilation at enrollment, using permuted blocks with concealed allocation. Each study arm consists of two components: composition of fluid creep (diluents and line patency solutions) and composition of maintenance fluids. All fluids are market-authorized products prepared and blinded by hospital pharmacy, supplied in opaque bags labeled only with trial codes. The assigned strategy is maintained throughout the ICU stay or until blinded study fluids are no longer available under the rotating allocation schedule. Follow-up continues until day 90 after ICU admission
Not provided
Not provided
Blinding is ensured by the use of opaque blinding labels applied by unblinded hospital pharmacists. These labels conceal the identity of the solution while leaving mandatory information such as fluid volume, batch number, and expiry date visible, in line with regulatory requirements. The fluids are otherwise indistinguishable and are labeled only with a randomization code letter. Randomization letters are changed monthly to prevent recognition of fluid composition. Only the pharmacists are unblinded; they handle labeling, storage, and distribution but are not involved in patient care or outcome assessment. In the ICU, nurses and physicians administer fluids documented simply as "study fluid," without access to the underlying composition.
| NaCl 0.9% (normal saline) for fluid creep | Drug |
|
|
| PlasmaLyte as maintenance fluid | Drug |
|
|
| NaCl 0.3% in glucose 3.3% as maintenance fluid | Drug |
|
|
| From randomization until ICU discharge (up to day 90 counted from ICU admission) |
| Occurrence of moderate and severe hypernatremia | Defined as the number of participants with at least one episode of: Moderate hypernatremia: serum sodium 151-155 mmol/L Severe hypernatremia: serum sodium >155 mmol/L To be counted as an event, the sodium level must increase by at least 3 mmol/L from baseline to account for pre-existing mild hypernatremia and analytical variation. Assessments are based on daily routine morning serum sodium values from the central laboratory (ion-specific electrode). If available, paired serum albumin and point-of-care sodium values (measured within 2 hours of the central measurement) will be recorded to allow cross-checks and sensitivity analyses. | From randomization until ICU discharge (up to day 90 counted from ICU admission) |
| Occurrence of moderate and severe hyperchloremia | Defined as the number of participants with at least one episode of: Moderate hyperchloremia: serum chloride 111-115 mmol/L Severe hyperchloremia: serum chloride >115 mmol/L To be counted as an event, the chloride level must increase by at least 2 mmol/L from baseline to account for pre-existing mild hyperchloremia and analytical variation. Assessments are based on daily routine morning serum chloride values from the central laboratory (ion-specific electrode). If available, paired serum albumin and point-of-care chloride values (measured within 2 hours of the central measurement) will be recorded to allow cross-checks and sensitivity analyses | From randomization until ICU discharge (up to day 90 counted from ICU admission) |
| Time to first administration of intravenous loop diuretic | Defined as the time (in hours) from randomization until the first administration of an intravenous loop diuretic (e.g., furosemide or bumetanide). The exact timestamp of first administration is recorded. | From randomization until ICU discharge (up to day 90 counted from ICU admission) |
| Proportion of ICU days with intravenous loop diuretic use | Defined as the number of ICU days during which a participant receives at least one dose of an intravenous loop diuretic, expressed as a proportion of total ICU days. | From randomization until ICU discharge (up to day 90 counted from ICU admission) |
| Cumulative fluid balance in mL up to first IV loop diuretic use | Defined as the cumulative net fluid balance, excluding insensible losses. Daily fluid balance is calculated as total inputs minus total outputs (mL per ICU day). Inputs: study fluids, non-study fluid creep, non-study maintenance and replacement fluids, non-study resuscitation fluids, enteral and parenteral nutrition, blood products, and oral intake. Outputs: urine output, net ultrafiltration by renal replacement therapy, gastric aspirates, drain outputs, and diarrhea (if precisely measured). The cumulative fluid balance is the sum of all daily fluid balances from ICU admission until the morning of the first ICU day on which an intravenous loop diuretic is prescribed. | From ICU admission until ICU discharge (up to day 90 counted from ICU admission) |
| Occurrence of hyperglycemia | Defined as the proportion of glucose measurements >180 mg/dL relative to the total number of glucose assessments during the ICU stay. Mean daily glucose values will also be calculated for each ICU day. Assessments are based on point-of-care blood gas analyzer values, which are routinely collected multiple times per day in all ICU patients. | From randomization until ICU discharge (up to day 90 counted from ICU admission) |
| Occurrence of hypoglycemia | Defined as the number of participants with at least one episode of hypoglycemia, serum glucose <70 mg/dL, measured on routine point-of-care blood gas analysis. Severe hypoglycemia (<40 mg/dL) is separately recorded as a serious adverse reaction. | From randomization until ICU discharge (up to day 90 counted from ICU admission) |
| Occurrence of new-onset acute kidney injury (AKI) | Defined as the number of participants who develop new-onset AKI stage 2 or 3 according to KDIGO criteria (Kidney Disease: Improving Global Outcomes), starting from the third ICU day after randomization. AKI classification is based on daily serum creatinine (central laboratory morning samples) and urine output collected every 12-24 hours. KDIGO stage 1 is not assessed in this trial. | From third ICU day after randomization until ICU discharge (up to day 90 counted from ICU admission) |
| Occurrence of new-onset need for renal replacement therapy (RRT) | Defined as the number of participants requiring new initiation of RRT (continuous renal replacement therapy, peritoneal dialysis, or intermittent hemodialysis). To attribute RRT to the intervention, only events starting on or after the second ICU day following randomization are considered. | From the second ICU day after randomization until ICU discharge (up to day 90 counted from ICU admission) |
| Renal replacement therapy-free days at day 90 | Calculated as the number of days during the 90-day observation period that a participant is alive and not receiving renal replacement therapy (RRT). For intermittent hemodialysis, periods with up to 3 days between sessions are counted as days on RRT. | From ICU admission until day 90 counted from ICU admission. |
| Occurrence of new-onset need for mechanical ventilation | Defined as the number of participants who newly require mechanical ventilation after randomization. Mechanical ventilation includes invasive and noninvasive ventilation (including continuous positive airway pressure (CPAP)) but excludes high-flow nasal oxygen. To attribute events to the intervention, only new initiation from the second ICU day after randomization is considered. | From the second ICU day after randomization until ICU discharge (up to day 90 counted from ICU admission) |
| Ventilator-free days at day 90 | Calculated as the number of days during the 90-day observation period that a participant is alive and free of mechanical ventilation. Mechanical ventilation includes invasive and noninvasive ventilation (including CPAP) but excludes high-flow nasal oxygen. Following extubation, days are counted as ventilator-free only if no re-intubation occurs within 48 hours. | From ICU admission until ICU discharge (up to day 90 counted from ICU admission) |
| Days alive and out of hospital at day 90 (DAOH90) | Defined as the number of days a participant is alive and outside the hospital during the 90 days after ICU admission. If a patient is discharged and later readmitted, both admissions are included in the total number of hospitalization days. Mortality is penalized and assigned a value of zero DAOH. DAOH is calculated at day 90 counted from ICU admission. | From ICU admission until day 90 counted from ICU admission. |
| ICU length of stay | Defined as the number of calendar days from ICU admission to ICU discharge, including referral or transfer to other ICUs following the same admission. | From ICU admission until ICU discharge (up to day 90 counted from ICU admission). |
| Hospital length of stay | Defined as the number of calendar days from ICU admission to hospital discharge, including transfers to other hospitals. Discharges or transfers to rehabilitation wards within the same hospital are not counted as hospital length of stay. | From ICU admission until hospital discharge (up to day 90 counted from ICU admission) |
| ICU mortality | Death occurring at any time while continuously in ICU during the index (initial) ICU episode. Inter-ICU transfers are considered part of the same continuous ICU episode. Deaths after discharge from the index ICU episode-whether on the ward or during any later ICU readmission within the same hospital admission-are not counted. | From ICU admission until discharge from the index ICU episode, including any continuous referrals/transfers to other ICUs (up to day 90 counted from ICU admission) |
| Hospital mortality | Death occurring at any time during the index (initial) hospital admission, irrespective of location (ICU or ward within the same hospital) and including transfers to other hospitals within the same continuous admission. Deaths after discharge from the index hospital admission are not counted, even if the patient is readmitted later. | From ICU admission until discharge from the index hospital admission (up to day 90 counted from ICU admission) |
| Cumulative sodium, chloride and glucose administration | Running total of sodium, chloride, and glucose (mmol or g) from ICU admission onward. Each day's administered amount is added to all previous ICU days. Same sources and exclusions as for daily administration. | From ICU admission until ICU discharge (up to day 90 counted from ICU admission). |
| Daily fluid balance (mL) | Daily fluid balance is calculated as inputs minus outputs (mL per ICU Day). Inputs: study fluids, non-study fluid creep, non-study maintenance and replacement fluids, non-study resuscitation fluids, enteral and parenteral nutrition, blood products, and oral intake. Outputs: urine output, net ultrafiltration by renal replacement therapy, gastric aspirates, drain outputs, and diarrhea (if precisely measured). From the time renal replacement therapy or intravenous loop diuretics are initiated, fluid balance will be analyzed separately from patients who do not receive these interventions. | From ICU admission until ICU discharge, day 90 counted from ICU admission, removal of bladder catheter or initiation of bladder irrigation, whichever comes first. |
| Cumulative fluid balance (mL) | Cumulative fluid balance is defined as the running total of daily net fluid balances (inputs minus outputs), excluding insensible losses. Each day's balance is added to that of all previous ICU days, allowing assessment at any time during the ICU stay. Daily fluid balance is calculated as inputs minus outputs (mL per ICU Day). Inputs: study fluids, non-study fluid creep, non-study maintenance and replacement fluids, non-study resuscitation fluids, enteral and parenteral nutrition, blood products, and oral intake. Outputs: urine output, net ultrafiltration by renal replacement therapy, gastric aspirates, drain outputs, and diarrhea (if precisely measured). From the time renal replacement therapy or intravenous loop diuretics are initiated, fluid balance will be analyzed separately from patients who do not receive these interventions. | From ICU admission until ICU discharge, day 90 counted from ICU admission, removal of bladder catheter or initiation of bladder irrigation, whichever comes first. |
| Serum urea-to-creatinine ratio | Defined as the change in serum urea-to-creatinine ratio, measured every other ICU day starting the first morning after randomization in patients not receiving renal replacement therapy (RRT). Serum creatinine is assessed as part of routine care, and serum urea is measured from the same morning blood sample without additional sampling. Urea measurements are discontinued from the day RRT is initiated, and patients on RRT are excluded from this analysis. This endpoint is exploratory and based on the rationale that higher sodium exposure, as in the NaCl-rich arm, may increase muscle catabolism. The serum urea-to-creatinine ratio is an established biomarker of catabolism in critically ill patients. | From the first morning after randomization until ICU discharge or initiation of RRT (up to day 90). |
| Daily sodium and chloride balance (SALADIN substudy) | Net daily balance of sodium and chloride (mmol per ICU day), defined as inputs minus outputs. Inputs: study fluids, non-study maintenance and replacement fluids and resuscitation fluids, enteral and parenteral nutrition, and blood products (sodium/chloride content estimated from reference values). Excludes non-study fluid creep and oral intake. Outputs: sodium and chloride content of all urine collected during the ICU day Urine samples are performed until the ICU day on which bladder catheter removal, initiation of bladder irrigation, start of renal replacement therapy, or ICU discharge occurs, whichever comes first. | From ICU admission until ICU discharge or end of substudy sampling (up to day 90 counted from ICU admission) |
| Cumulative sodium and chloride balance (SALADIN substudy) | Running total of daily sodium and chloride balances. Each day's balance is added to that of all previous ICU days, allowing assessment at any time during the ICU stay. Net daily balance of sodium and chloride (mmol per ICU day), defined as inputs minus outputs. Inputs: study fluids, non-study maintenance and replacement fluids and resuscitation fluids, enteral and parenteral nutrition, and blood products (sodium/chloride content estimated from reference values). Excludes non-study fluid creep and oral intake. Outputs: sodium and chloride content of all urine collected during the ICU day Urine samples are performed until the ICU day on which bladder catheter removal, initiation of bladder irrigation, start of renal replacement therapy, or ICU discharge occurs, whichever comes first. | From ICU admission until ICU discharge or end of substudy sampling (up to day 90 counted from ICU admission) |
| Solute-free water clearance (SALADIN substudy) | Derived from urine and plasma osmolality and urine flow rate. Reported as mL per ICU day. Formula: Solute-free water clearance CH2O = V × (1 - Uosm/Posm), where V = urine flow rate, Uosm = urine osmolality, and Posm = plasma osmolality. Calculated daily during ICU stay in participants with 24-hour urine collections. | From ICU admission until ICU discharge or end of substudy sampling (up to day 90 counted from ICU admission) |
| Electrolyte-free water clearance (SALADIN substudy) | Derived from urine sodium, urine potassium, plasma sodium, and urine flow rate. Reported as mL per ICU day. Formula Electrolyte-free water clearance: CeH2O = V × (1 - (UNa + UK)/PNa)), where V = urine flow rate, UNa = urine sodium concentration, UK = urine potassium concentration, and PNa = plasma sodium concentration. Calculated daily during ICU stay in participants with 24-hour urine collections. | From ICU admission until ICU discharge or end of substudy sampling (up to day 90 counted from ICU admission) |
| Volume kinetics (SALADIN substudy) | Model-based analysis of administered fluid volumes and urine output to describe distribution and clearance of infused solutions. Performed in participants included in the SALADIN substudy with complete fluid and urine balance data. | From ICU admission until ICU discharge or end of substudy sampling (up to day 90 counted from ICU admission) |
| Measured body weight (SALADIN substudy) | Daily body weight recorded in substudy participants to quantify changes in body fluid volume and tissue mass during critical illness. | From ICU admission until ICU discharge or end of substudy sampling (up to day 90 counted from ICU admission) |
| Fluid distribution (BIA-derived) (SALADIN substudy) | Noninvasive bioelectrical impedance analysis (BIA) will be performed once daily up to every third ICU day in substudy participants using a multi-frequency analyzer. Fluid distribution parameters assessed include total body water, intracellular water, extracellular water, intravascular and extravascular distribution, and volume excess. Results are used to evaluate dynamic changes in fluid status during critical illness and to relate these to sodium and chloride balance. | From randomization until ICU discharge or end of substudy sampling (up to day 90 counted from ICU admission) |
| Body Composition (BIA-derived) (SALADIN-substudy) | Noninvasive bioelectrical impedance analysis (BIA) will be performed once daily up to every third ICU day in substudy participants using a multi-frequency analyzer. Body composition parameters assessed include fat-free mass, fat mass, muscle mass, protein, mineral, and bone content. Serial measurements are used to assess changes in tissue composition over the course of critical illness. | From randomization until ICU discharge or end of substudy sampling (up to day 90 counted from ICU admission) |
| Metabolic Indices (BIA-derived) (SALADIN substudy) | Noninvasive bioelectrical impedance analysis (BIA) will be performed once daily up to every third ICU day in substudy participants using a multi-frequency analyzer. Metabolic indices include resting metabolic rate, glycogen deposits, phase angle, and malnutrition index. These indices are evaluated to explore metabolic changes and nutritional status during critical illness, and their relationship with sodium and chloride balance. | From randomization until ICU discharge or end of substudy sampling (up to day 90 counted from ICU admission) |
| Recruiting |
| Antwerp |
| 2030 |
| Belgium |
| Antwerp University Hopsital (UZA) | Not yet recruiting | Edegem | 2650 | Belgium |
| ZAS Paflijn | Not yet recruiting | Merksem | 2170 | Belgium |
| Van Regenmortel N, Verbrugghe W, Roelant E, Van den Wyngaert T, Jorens PG. Maintenance fluid therapy and fluid creep impose more significant fluid, sodium, and chloride burdens than resuscitation fluids in critically ill patients: a retrospective study in a tertiary mixed ICU population. Intensive Care Med. 2018 Apr;44(4):409-417. doi: 10.1007/s00134-018-5147-3. Epub 2018 Mar 27. |
| 33999276 | Background | Van Regenmortel N, Moers L, Langer T, Roelant E, De Weerdt T, Caironi P, Malbrain MLNG, Elbers P, Van den Wyngaert T, Jorens PG. Fluid-induced harm in the hospital: look beyond volume and start considering sodium. From physiology towards recommendations for daily practice in hospitalized adults. Ann Intensive Care. 2021 May 17;11(1):79. doi: 10.1186/s13613-021-00851-3. |
| 31576437 | Background | Van Regenmortel N, Hendrickx S, Roelant E, Baar I, Dams K, Van Vlimmeren K, Embrecht B, Wittock A, Hendriks JM, Lauwers P, Van Schil PE, Van Craenenbroeck AH, Verbrugghe W, Malbrain MLNG, Van den Wyngaert T, Jorens PG. 154 compared to 54 mmol per liter of sodium in intravenous maintenance fluid therapy for adult patients undergoing major thoracic surgery (TOPMAST): a single-center randomized controlled double-blind trial. Intensive Care Med. 2019 Oct;45(10):1422-1432. doi: 10.1007/s00134-019-05772-1. Epub 2019 Oct 1. |
| 16304249 | Background | Sakr Y, Vincent JL, Reinhart K, Groeneveld J, Michalopoulos A, Sprung CL, Artigas A, Ranieri VM; Sepsis Occurence in Acutely Ill Patients Investigators. High tidal volume and positive fluid balance are associated with worse outcome in acute lung injury. Chest. 2005 Nov;128(5):3098-108. doi: 10.1378/chest.128.5.3098. |
| 27734109 | Background | Silversides JA, Major E, Ferguson AJ, Mann EE, McAuley DF, Marshall JC, Blackwood B, Fan E. Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. Intensive Care Med. 2017 Feb;43(2):155-170. doi: 10.1007/s00134-016-4573-3. Epub 2016 Oct 12. |
| 28143505 | Background | Salahuddin N, Sammani M, Hamdan A, Joseph M, Al-Nemary Y, Alquaiz R, Dahli R, Maghrabi K. Fluid overload is an independent risk factor for acute kidney injury in critically Ill patients: results of a cohort study. BMC Nephrol. 2017 Feb 1;18(1):45. doi: 10.1186/s12882-017-0460-6. |
| 30482136 | Background | Bihari S, Prakash S, Potts S, Matheson E, Bersten AD. Addressing the inadvertent sodium and chloride burden in critically ill patients: a prospective before-and-after study in a tertiary mixed intensive care unit population. Crit Care Resusc. 2018 Dec;20(4):285-293. |
| 29727367 | Background | Magee CA, Bastin MLT, Laine ME, Bissell BD, Howington GT, Moran PR, McCleary EJ, Owen GD, Kane LE, Higdon EA, Pierce CA, Morris PE, Flannery AH. Insidious Harm of Medication Diluents as a Contributor to Cumulative Volume and Hyperchloremia: A Prospective, Open-Label, Sequential Period Pilot Study. Crit Care Med. 2018 Aug;46(8):1217-1223. doi: 10.1097/CCM.0000000000003191. |
| 34798374 | Background | Van Regenmortel N, Langer T, De Weerdt T, Roelant E, Malbrain M, Van den Wyngaert T, Jorens P. Effect of sodium administration on fluid balance and sodium balance in health and the perioperative setting. Extended summary with additional insights from the MIHMoSA and TOPMAST studies. J Crit Care. 2022 Feb;67:157-165. doi: 10.1016/j.jcrc.2021.10.022. Epub 2021 Nov 17. |
| 30806785 | Background | Nagae M, Egi M, Furushima N, Okada M, Makino S, Mizobuchi S. The impact of intravenous isotonic and hypotonic maintenance fluid on the risk of delirium in adult postoperative patients: retrospective before-after observational study. J Anesth. 2019 Apr;33(2):287-294. doi: 10.1007/s00540-019-02626-4. Epub 2019 Feb 26. |
| 31891467 | Background | Surveillance report 2017 - Intravenous fluid therapy in adults in hospital (2013) NICE guideline CG174 [Internet]. London: National Institute for Health and Care Excellence (NICE); 2017 Apr 24. No abstract available. Available from http://www.ncbi.nlm.nih.gov/books/NBK552079/ |
| 31531715 | Background | Haines RW, Zolfaghari P, Wan Y, Pearse RM, Puthucheary Z, Prowle JR. Elevated urea-to-creatinine ratio provides a biochemical signature of muscle catabolism and persistent critical illness after major trauma. Intensive Care Med. 2019 Dec;45(12):1718-1731. doi: 10.1007/s00134-019-05760-5. Epub 2019 Sep 17. |
| 28414295 | Background | Kitada K, Daub S, Zhang Y, Klein JD, Nakano D, Pedchenko T, Lantier L, LaRocque LM, Marton A, Neubert P, Schroder A, Rakova N, Jantsch J, Dikalova AE, Dikalov SI, Harrison DG, Muller DN, Nishiyama A, Rauh M, Harris RC, Luft FC, Wassermann DH, Sands JM, Titze J. High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation. J Clin Invest. 2017 May 1;127(5):1944-1959. doi: 10.1172/JCI88532. Epub 2017 Apr 17. |
| 28414302 | Background | Rakova N, Kitada K, Lerchl K, Dahlmann A, Birukov A, Daub S, Kopp C, Pedchenko T, Zhang Y, Beck L, Johannes B, Marton A, Muller DN, Rauh M, Luft FC, Titze J. Increased salt consumption induces body water conservation and decreases fluid intake. J Clin Invest. 2017 May 1;127(5):1932-1943. doi: 10.1172/JCI88530. Epub 2017 Apr 17. |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 5, 2025 | Sep 8, 2025 | SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form: CRUSADERS main trial | Mar 8, 2025 | Sep 7, 2025 | ICF_002.pdf |
| ICF | No | No | Yes | Informed Consent Form: SALADIN nested substudy | Mar 19, 2025 | Sep 7, 2025 | ICF_003.pdf |
| ID | Term |
|---|---|
| D016638 | Critical Illness |
| D058186 | Acute Kidney Injury |
| D007010 | Hyponatremia |
| ID | Term |
|---|---|
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D051437 | Renal Insufficiency |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D014883 | Water-Electrolyte Imbalance |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D005947 | Glucose |
| D000077330 | Saline Solution |
| C048013 | Plasmalyte A |
| ID | Term |
|---|---|
| D006601 | Hexoses |
| D009005 | Monosaccharides |
| D000073893 | Sugars |
| D002241 | Carbohydrates |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
Not provided
Not provided