Evaluation of Sodium Chloride and Glucose Monohydrate Infusion Strategies in Critically Ill Patients: Impact on Mortality and Organ Support

The primary objective of the study is to evaluate whether a strategy of reducing the **sodium chloride** burdens in critically ill adult patients by targeting the sodium and chloride content of fluid creep and maintenance fluids leads to improved outcomes in terms of mortality and the need for respiratory and renal organ support. This is clinically relevant as it may offer a more effective approach to managing fluid and electrolyte balance in critically ill patients, potentially reducing complications and improving survival rates.

Secondary objectives include:

• Assessing whether the strategy is non-inferior to isotonic solutions in terms of the incidence of moderate and severe hyponatremia, with a non-inferiority margin for severe hyponatremia (< 125 mmol/L) of 5%, and in the incidence of hyperglycemia. Additionally, evaluating if the intervention results in a lower incidence of moderate and severe hypernatremia, hyperchloremia, and hypoglycemia.
• Determining if the strategy results in a lower cumulative fluid balance before administration of IV loop diuretics and a delayed and reduced need for IV loop diuretics to manage fluid retention.
• Evaluating if the strategy results in a lower incidence of acute kidney injury, a reduced new-onset need for renal replacement therapy, and a shorter duration of renal replacement therapy.
• Investigating if the strategy results in a lower new-onset need for mechanical ventilation and a shorter duration of mechanical ventilation.
• Assessing if the strategy results in reduced ICU and hospital mortality and shorter ICU and hospital lengths of stay.
• Determining if the strategy results in substantially lower sodium and chloride burdens and subsequently lower cumulative fluid balances.
• Evaluating if the strategy results in a lower level of catabolism and muscle wasting.
• Conducting a nested substudy, SALADIN, in a targeted 150 patients to investigate detailed sodium and chloride balances, providing additional physiological insights.
• Correlating findings with cumulative fluid balance, solute- and electrolyte-free water clearance, assessments of volume kinetics, bioelectrical impedance analysis, and measured body weight.

The clinical trial involves **critically ill patients** admitted to the Intensive Care Unit (ICU) for medical or surgical emergencies, including complications of elective surgery. The study population includes both male and female adults, aged 18 years and older, who are expected to require ICU care for at least two days, indicating a severe or complex condition at enrollment. Participants are anticipated to receive a minimum of 300 mL of fluid creep or at least 1L of maintenance fluid within the first 24 hours post-inclusion, depending on the study arm. The trial population is considered vulnerable due to their critical health status. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the impact of reducing **sodium chloride** burdens in critically ill adult patients by targeting the sodium and chloride content of fluid creep and maintenance fluids. This study employs a randomized, double-blind, controlled trial design to ensure the reliability and validity of the results. The trial is expected to commence on June 1, 2025, and conclude by January 1, 2028, with a maximum treatment period of 28 days for each participant. The primary endpoint is the number of days alive and without life support at 90 days post-ICU admission, while secondary endpoints include occurrences of electrolyte imbalances, fluid retention, acute kidney injury, and other clinical outcomes.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (at least 18 years), ICU admission for medical or surgical emergencies, and expected fluid requirements. Follow-up visits will be conducted to monitor the administration of study fluids and assess clinical outcomes. The end-of-study visit will evaluate the primary and secondary endpoints. The expected length of participant involvement is up to 28 days, with conditions for early termination including withdrawal of consent or adverse events that compromise patient safety.

The trial will utilize intravenous administration of authorized solutions, including **sodium chloride**, **glucose monohydrate**, and other electrolytes, which are standard in ICU settings. The study is classified as low-intervention, as the investigational medicinal products are used in accordance with their marketing authorization, and additional procedures align with routine care. The trial will be conducted in an ICU environment, ensuring continuous monitoring and care by trained healthcare professionals. This comprehensive approach aims to maintain patient safety throughout the study duration.

The clinical trial involves the administration of several **intravenous** solutions, each with distinct compositions and purposes. The first experimental medication is **Natriumchloride 0.9% w/v, Viaflo**, a solution for infusion containing **sodium chloride** as the active substance. This solution is administered intravenously with a maximum daily dose of 3 liters and a total maximum dose of 84 liters over a treatment period of 28 days. The solution is provided by Baxter SA and is classified under the ATC code B05XX, indicating its use as an intravenous solution additive.

The second treatment is **NaCl 0.3% w/v + Glucose 3.3% w/v Viaflo**, a solution for intravenous infusion containing both **sodium chloride** and **glucose monohydrate**. This solution is also administered intravenously, with the same dosing schedule as the first treatment: a maximum of 3 liters per day and a total of 84 liters over 28 days. It is categorized under the ATC code B05BB02, which denotes electrolytes with carbohydrates.

The third solution used in the trial is **Glucose 5% w/v, Viaflo**, which contains **glucose monohydrate** as the active ingredient. This solution is administered intravenously, with a dosing regimen identical to the previous solutions, allowing for a maximum of 3 liters per day and a total of 84 liters over the course of 28 days. It falls under the ATC code B05BA03, indicating its classification as a carbohydrate solution.

The final experimental medication is **Plasmalyte A Viaflo**, a complex solution for infusion containing multiple active substances: **magnesium chloride hexahydrate**, **potassium chloride**, **sodium chloride**, **sodium acetate trihydrate**, and **sodium gluconate**. This solution is administered intravenously, adhering to the same dosing limits as the other treatments, with a maximum daily dose of 3 liters and a total maximum dose of 84 liters over 28 days. It is classified under the ATC code B05BB01, which pertains to electrolytes.

All solutions are provided by Baxter SA and are not formulated for pediatric use. The trial does not involve any orphan drug designations, and the solutions are used as part of a strategy to reduce sodium chloride burdens in critically ill adult patients. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

The efficacy of the CRUSADERS clinical trial will be assessed using a primary endpoint and several secondary endpoints. The primary endpoint is the number of **Days Alive and Without Life Support (DAWOLS)** at 90 days following ICU admission. This measure will provide insight into the overall survival and independence from life support systems in critically ill adult patients.

Secondary endpoints include the occurrence of moderate and severe **hyponatremia**, **hypernatremia**, and **hyperchloremia**. Additionally, fluid retention, diuretic use, and the occurrence of **hyperglycemia** and **hypoglycemia** will be monitored. The trial will also evaluate the incidence of acute kidney injury, the need for mechanical ventilation, and overall mortality and length of stay in the ICU. Daily and cumulative administration of sodium, chloride, and glucose from all sources, excluding non-study fluid creep and oral intake, will be recorded. Fluid balance will be assessed daily and cumulatively on ICU days, with specific considerations for patients undergoing renal replacement therapy (RRT) or receiving intravenous loop diuretics.

Data collection will occur continuously throughout the ICU stay, with specific attention to the interventions and their impact on the outlined endpoints. The trial will be conducted in an ICU setting, ensuring comprehensive monitoring and care by trained ICU personnel. This approach will facilitate accurate and reliable assessment of the efficacy parameters, contributing to the overall evaluation of the trial's outcomes.