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

NCT07189091 | Recruiting Phase 4 DMC

• 2 other identifiers: Edge 0038132025-520744-14-00
• Study Type: interventional
• Target: 640
• Locations: 1 country
• Sites: 4

Brief Summary

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

Conditions

Fluid and Electrolyte Imbalance; Critical Illness; Fluid Balance Outcomes; Critical Care, Intensive Care; Fluid Accumulation

Keywords

Intensive Care Unit; Critically Ill; Critical Illness; Intravenous fluids; Maintenance fluids; Fluid Creep; Sodium chloride reduction; Salt reduction; Hypotonic fluids; Saline (NaCl 0.9%); Fluid balance; Electrolyte disorders; Glycemic control; Acute kidney injury; Mechanical ventilation; Organ support; Hyponatremia

Outcome Measures

Primary Outcomes (1)

• 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)

Secondary Outcomes (18)

• Occurrence of moderate and severe hyponatremia

  From randomization until ICU discharge (up to day 90 counted from ICU admission)

• Occurrence of moderate and severe hypernatremia

  From randomization until ICU discharge (up to day 90 counted from ICU admission)

• Occurrence of moderate and severe hyperchloremia

  From randomization until ICU discharge (up to day 90 counted from ICU admission)

• Time to first administration of intravenous loop diuretic

  From randomization until ICU discharge (up to day 90 counted from ICU admission)

• Proportion of ICU days with intravenous loop diuretic use

  From randomization until ICU discharge (up to day 90 counted from ICU admission)

Other Outcomes (14)

• Daily sodium, chloride and glucose administration

  From ICU admission until ICU discharge (up to day 90 counted from ICU admission).

• Cumulative sodium, chloride and glucose administration

  From ICU admission until ICU discharge (up to day 90 counted from ICU admission).

• Daily fluid balance (mL)

  From ICU admission until ICU discharge, day 90 counted from ICU admission, removal of bladder catheter or initiation of bladder irrigation, whichever comes first.

Study Arms (2)

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%

Drug: Glucose 5% for fluid creep; Drug: NaCl 0.3% in glucose 3.3% as maintenance fluid

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

Drug: NaCl 0.9% (normal saline) for fluid creep; Drug: PlasmaLyte as maintenance fluid

Interventions

Glucose 5% for fluid creep DRUG

* 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%

Sodium chloride reduction strategy, the NaCl-poor arm

NaCl 0.9% (normal saline) for fluid creep DRUG

* 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%.

Isotonic fluid strategy, the NaCl-rich arm

PlasmaLyte as maintenance fluid DRUG

* 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.

Isotonic fluid strategy, the NaCl-rich arm

NaCl 0.3% in glucose 3.3% as maintenance fluid DRUG

* 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

Sodium chloride reduction strategy, the NaCl-poor arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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)

Sponsors & Collaborators

• University Hospital, Antwerp: lead
• Ziekenhuis aan de Stroom: collaborator
• Research Foundation Flanders: collaborator

Study Sites (4)

ZAS Middelheim

Antwerp, 2020, Belgium

NOT YET RECRUITING

ZAS Cadix

Antwerp, 2030, Belgium

RECRUITING

Antwerp University Hopsital (UZA)

Edegem, 2650, Belgium

NOT YET RECRUITING

ZAS Paflijn

Merksem, 2170, Belgium

NOT YET RECRUITING

Related Publications (15)

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• 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 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.

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• 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.

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• 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.

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• 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 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.

  PMID: 29727367 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.

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• 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.

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• 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/

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• 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.

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• 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.

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• 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.

  PMID: 28414302 BACKGROUND

MeSH Terms

Conditions

Critical Illness; Acute Kidney Injury; Hyponatremia

Interventions

Glucose; Saline Solution; Plasmalyte A

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Water-Electrolyte Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Hexoses; Monosaccharides; Sugars; Carbohydrates; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Niels Van Regenmortel, MD, PhD

  Ziekenhuis aan de Stroom (ZAS) Network of Hospitals

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Petra Y Vertongen

CONTACT

+3238214404; petra.vertongen@uza.be

Leen Ameryckx

CONTACT

+3232757005; leen.ameryckx@uza.be

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: August 25, 2025
• First Posted: September 23, 2025
• Study Start: October 7, 2025
• Primary Completion (Estimated): April 30, 2028
• Study Completion (Estimated): July 30, 2028
• Last Updated: February 3, 2026

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

BE (4)