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

Official title

Effect of Reduced Sodium Chloride in Fluid Creep and Maintenance Fluids in Critically Ill Adults: A Randomized Controlled Trial

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

Detailed description

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

• Drug Glucose 5% for fluid creep
  * 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%
• Drug NaCl 0.9% (normal saline) for fluid creep
  * 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%.
• Drug PlasmaLyte as maintenance fluid
  * 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.
• Drug NaCl 0.3% in glucose 3.3% as maintenance fluid
  * 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 bo

Primary outcome measures

• Days alive and without life support at day 90 (DAWOLS90) [Time frame: From admission until day 90 counted from ICU admission (= Day 1)]

Secondary outcome measures (12)

• Occurrence of moderate and severe hyponatremia [Time frame: From randomization until ICU discharge (up to day 90 counted from ICU admission)]
• Occurrence of moderate and severe hypernatremia [Time frame: From randomization until ICU discharge (up to day 90 counted from ICU admission)]
• Occurrence of moderate and severe hyperchloremia [Time frame: From randomization until ICU discharge (up to day 90 counted from ICU admission)]
• Time to first administration of intravenous loop diuretic [Time frame: From randomization until ICU discharge (up to day 90 counted from ICU admission)]
• Proportion of ICU days with intravenous loop diuretic use [Time frame: 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 [Time frame: From ICU admission until ICU discharge (up to day 90 counted from ICU admission)]
• Occurrence of hyperglycemia [Time frame: From randomization until ICU discharge (up to day 90 counted from ICU admission)]
• Occurrence of hypoglycemia [Time frame: From randomization until ICU discharge (up to day 90 counted from ICU admission)]
• Occurrence of new-onset acute kidney injury (AKI) [Time frame: 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) [Time frame: 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 [Time frame: From ICU admission until day 90 counted from ICU admission.]
• Occurrence of new-onset need for mechanical ventilation [Time frame: From the second ICU day after randomization until ICU discharge (up to day 90 counted from ICU admission)]

Eligibility criteria

Inclusion criteria

• At least 18 years of age
• Patients who are admitted to the ICU for medical or surgical emergencies, including complications of elective surgery
• The treating physician expects the patient will still require ICU care in two days, indicating a severe or complex condition at enrollment
• 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

• 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.
• Hyponatremia below 131 mmol/L at admission
• 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.
• Patient's death is deemed imminent and inevitable, admission for palliative care or admission solely for organ donation
• Patient receiving chronic renal replacement therapy
• Patients referred after a stay of more than 24 hours in another ICU
• Patients randomized in CRUSADERS before
• 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

• Patients expected to require renal replacement therapy within 24 hours
• Increased insensible fluid losses: burns, extensive wounds or skin defects or massive diarrhea,…
• Patients without a urine catheter
• Patients expected to require bladder irrigation within 24 hours
• Patients on chronic treatment with loop or thiazide diuretics (including combination preparations)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Belgium · 4 centers

• ZAS Middelheim — Antwerp
• ZAS Cadix — Antwerp
• Antwerp University Hopsital (UZA) — Edegem
• ZAS Paflijn — Merksem

Publications

• 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. PMID 36915265
• 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. PMID 29589054
• 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. PMID 33999276
• 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 contr PMID 31576437
• 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. PMID 16304249
• 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. PMID 27734109
• 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. PMID 28143505
• 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. PMID 30482136

Identifiers

NCT: NCT07189091 · Edge 003813 · 2025-520744-14-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗