CReep and Maintenance flUid Sodium Chloride ADministration rEduction in cRitically Ill adultS

Phase 4RecruitingNCT07189091

University Hospital, Antwerp640 enrolled

Overview

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.

Interventions

Glucose 5% for fluid creepDRUG

* Medications, including concentrated electrolytes, are dissolved in glucose 5% except when another solvent is mandatory according to the responsible pharmacist. * Infusions to keep intravenous lines open are glucose 5%

NaCl 0.9% (normal saline) for fluid creepDRUG

* Medications, including concentrated electrolytes, are dissolved in NaCl 0.9% except when another solvent is mandatory according to the responsible pharmacist. * All infusions to keep intravenous lines open are NaCl 0.9%.

PlasmaLyte as maintenance fluidDRUG

* Type: Maintenance fluid is PlasmaLyte. Potassium chloride or potassium phosphate can be added (or administered separately) whenever deemed necessary. * Rate: at the discretion of the treating physician, typically 25-30 ml/kg of body weight with a maximum of 100 ml/hour, accounting for concomitant fluid sources such as nutrition and fluid creep. It is allowed to prescribe a higher volume of study maintenance fluids to include replacement if both study fluids are considered appropriate.

NaCl 0.3% in glucose 3.3% as maintenance fluidDRUG

* Type: maintenance fluid is NaCl 0.3% in glucose 3.3%. Potassium chloride or potassium phosphate can be added (or administered separately) at the discretion of the treating physician whenever necessary. * Rate: at the discretion of the treating physician, typically 25-30 ml/kg of body weight with a maximum of 100 ml/hour, accounting for concomitant fluid sources such as nutrition and fluid creep. It is allowed to prescribe a higher volume of study maintenance fluids to include replacement if both study fluids are considered appropriate

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion criteria 1. At least 18 years of age 2. Patients who are admitted to the ICU for medical or surgical emergencies, including complications of elective surgery 3. The treating physician expects the patient will still require ICU care in two days, indicating a severe or complex condition at enrollment 4. The patient is expected to receive at least 300 mL of fluid creep or at least 1 liter of maintenance fluid according to study-arm during the first 24h after inclusion Exclusion Criteria: 1. A contraindication to hypotonic fluids due to risk of brain edema (including traumatic brain injury, major stroke, intracranial/subarachnoid hemorrhage, meningoencephalitis, intracranial malignancies…), with the timing and clinical judgment left at the discretion of the treating physician. 2. Hyponatremia below 131 mmol/L at admission 3. Admission solely for treatment of fluid accumulation due to cardiac decompensation, without other acute medical conditions requiring ICU-level care. Note: Patients with heart failure as a comorbidity, those on chronic diuretic therapy, or presenting with edema/bilateral lung infiltrates due to other conditions (e.g., sepsis, pneumonia) are not excluded. 4. Patient's death is deemed imminent and inevitable, admission for palliative care or admission solely for organ donation 5. Patient receiving chronic renal replacement therapy 6. Patients referred after a stay of more than 24 hours in another ICU 7. Patients randomized in CRUSADERS before 8. Patient is co-enrolled in an unapproved concomitant ICU-trial or in any trial with an intervention that affects fluid administration or fluid balance Additional exclusion criteria for the SALADIN nested substudy 1. Patients expected to require renal replacement therapy within 24 hours 2. Increased insensible fluid losses: burns, extensive wounds or skin defects or massive diarrhea,… 3. Patients without a urine catheter 4. Patients expected to require bladder irrigation within 24 hours 5. Patients on chronic treatment with loop or thiazide diuretics (including combination preparations)

Outcomes

Primary Outcomes

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.

Time frame: From admission until day 90 counted from ICU admission (= Day 1)

Secondary Outcomes

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