Balanced Solutions and Plasma Electrolytes

Study Overview
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Brief Summary
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The administration of intravenous fluids is ubiquitous in the care of the critically ill. Commonly available isotonic crystalloid solutions contain a broad spectrum electrolyte compositions including a range chloride concentrations. Recent prospective, randomized trials have shown improved patient outcomes with the use of balanced crystalloids compared to saline. There have not been large randomized studies comparing acetate buffered balanced crystalloids to non-acetate buffered balanced crystalloids in the critically ill. BASE will be a pilot study for a large, cluster-randomized, multiple-crossover trial enrolling critically ill patients from the Medical ICU at Vanderbilt University from June 2018 until January 2019. The primary endpoint will be plasma bicarbonate concentration between Intensive Care Unit admission and hospital discharge.

Detailed Description
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BASE is a pilot, cluster-randomized, multiple-crossover trial of lactated Ringer's versus Normosol-R pH 7.4 with regard to plasma bicarbonate concentration between intensive care unit admission and hospital discharge among all patients admitted to the medical intensive care unit. Between June 2018 and January 2019, all patients admitted to the medical intensive care unit at Vanderbilt University Medical Center who are 18 years or older will be enrolled. The study will occur in one-month blocks. The medical intensive care unit (MICU) will be randomized to an initial fluid group (lactated Ringer's or Normosol). The assigned fluid will be used exclusively for all patients receiving isotonic crystalloid for the duration of the month-long block (except in the presence of pre-specified contraindications). The assigned study fluid will switch at the end of each month-long block such that half of hte months are assigned to lactated Ringer's and half of the months are assigned to Normosol-R pH 7.4. It is anticipated that around 2,000 patients will be enrolled from the medical ICU during the study period. The primary outcome analysis will be an intention-to-treat comparison of the primary outcome of bicarbonate concentration (mmol/L) between enrollment and 7 days after enrollment between the lactated Ringer's and Normosol-R groups using generalized estimating equations with a random effect for study period and accounting for repeated measures.

Official Title
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Balanced Solutions and Plasma Electrolytes in the Medical Intensive Care Unit

Conditions
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Critical Illness, Acidosis, Metabolic

Intervention / Treatment
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* Other: Lactated Ringer's
* Other: Normosol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients admitted to the Medical ICU during the study period (Enrolled patients who are discharged from the hospital are eligible again if they are readmitted to the Medical ICU during the study period) Exclusion Criteria: Age < 18 years old Prisoners

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lactated Ringer's<br>Patients in a MICU block randomized to lactated Ringer's will receive lactated Ringer's whenever isotonic intravenous fluid administration is ordered by the treating provider. | Other: Lactated Ringer's<br>* Lactated Ringer's will be used whenever an isotonic crystalloid is ordered<br>* Other names: Non-acetate buffered solution;|
| Active Comparator: Normosol<br>Patients in a MICU block randomized to Normosol will receive Normosol-R pH 7.4 whenever isotonic intravenous fluid administration is ordered by the treating provider. | Other: Normosol<br>* Normosol-R pH 7.4 will be used whenever an isotonic crystalloid is ordered<br>* Other names: Acetate buffered solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Bicarbonate Concentration | The primary outcome is a repeated measures variable of plasma bicarbonate concentration (mmol/L) between ICU admission and 7 days. | Between ICU admission and Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Bicarbonate Concentration < 20 mmol/L |  | Between ICU admission and Day 7 | 
| Lowest Plasma Bicarbonate Concentration |  | Between ICU admission and Day 7 | 
| Plasma Chloride Concentration > 110 mmol/L |  | Between ICU admission and Day 7 | 
| Plasma Chloride Concentration < 100 mmol/L |  | Between ICU admission and Day 7 | 
| Highest Plasma Chloride Concentration |  | Between ICU admission and Day 7 | 
| Change in Plasma Chloride Concentration from Baseline to Peak |  | Between ICU admission and Day 7 | 
| Plasma Sodium Concentration > 145 mmol/L |  | Between ICU admission and Day 7 | 
| Plasma Sodium Concentration < 135 mmol/L |  | Between ICU admission and Day 7 | 
| Plasma Potassium Concentration > 5.5 mmol/L |  | Between ICU admission and Day 7 | 
| Plasma values for Sodium, Potassium, Chloride, Bicarbonate, Blood Urea Nitrogen, Creatinine, Calcium, and Lactate |  | Between ICU admission and Hospital Discharge or 30 Days | 
| Strong Ion Difference | (Sodium + Potassium + Calcium) - (Chloride + Lactate) in mmol/L | Between ICU admission and Day 7 | 
| Arterial pH |  | Between ICU admission and Day 7 | 
| Arterial Standard Base Excess |  | Between ICU admission and Day 7 | 
| Major Adverse Kidney Events within 30 days | This composite outcome will be considered present if at least one of the following occur: (1) A patient dies prior to the earlier of hospital discharge or day 30; (2) A patient receives new renal replacement therapy between enrollment and day 30, or (3) A patient has persistent renal dysfunction at the earlier of hospital discharge or day 30 (persistent renal dysfunction is defined as ≥ 200% of creatinine from baseline) | 30 Days after Enrollment Censored at Hospital Discharge | 
| 30-Day In-Hospital Mortality |  | 30 Days after Enrollment Censored at Hospital Discharge | 
| New Renal Replacement Therapy | The initiation of any renal replacement therapy between enrollment and 30 days censored at hospital discharge in a patient not known to have previously received renal replacement therapy. | 30 Days after Enrollment Censored at Hospital Discharge | 
| Stage II or Higher Acute Kidney Injury | A patient will meet this outcome if they meet Kidney Disease Improving Global Outcomes (KDIGO) creatinine criteria for stage II acute kidney injury or higher | Between ICU admission and Day 7 | 
| Persistent Renal Dysfunction | Final creatinine value before discharge or 30 days after enrollment ≥ 200% of baseline creatinine. | 30 Days after Enrollment Censored at Hospital Discharge | 
| Total Volume of Blood Product Transfusion |  | Between ICU admission and Day 7 | 
| Dose of Vasopressor | Dose of vasopressor (in norepinephrine equivalents, µg/kg/min) | Between ICU admission and Day 7 | 
| Intensive Care Unit-Free Days | Intensive care unit-free days to day 28 (ICU-free days) will be defined as the number of days from the time of the patient's physical transfer out of the ICU until day 28 after enrollment. Patients who die prior to day 28 after enrollment received a value of 0 for ICU-free days. Patients who never transfer out of the ICU prior to day 28 after enrollment will receive a value of 0 for ICU-free days. Patients who transferred out of the ICU, return to the ICU, and are not subsequently transferred out of the ICU again before day 28 after enrollment will receive a value of 0 for ICU-free days. For patients who transfer out of the ICU, are readmitted to the ICU, and subsequently transfer out of the ICU again prior to day 28 after enrollment, ICU-free days will be awarded based on the time of the final transfer out of the ICU prior to day 28 after enrollment. | Between ICU admission and Day 28 | 
| Vasopressor-Free Days | Vasopressor-free days to day 28 will be defined as the number of days from the time of vasopressor cessation until day 28 after enrollment. Patients who die prior to day 28 after enrollment will receive a value of 0 for vasopressor-free days. Patients who never cease to receive vasopressors prior to day 28 after enrollment receive a value of 0 for vasopressor-free days. Patients who achieve vasopressor cessation, return to receiving vasopressors, and do not again achieve vasopressor cessation before day 28 after enrollment receive a value of 0 for vasopressor-free days. For patients who achieve vasopressor cessation, return to receiving vasopressors, and subsequently achieve cessation of vasopressors again prior to day 28 after enrollment, vasopressor-free days will be awarded based on the time of the final cessation of vasopressors prior to day 28 after enrollment. Survivors who never receive vasopressors received 28 vasopressor-free days. | Between ICU admission and Day 28 | 
| Renal Replacement Therapy-Free Days | Renal replacement therapy-free days to day 28 (RRT- free days) will be defined as the number of days from the time of the final RRT treatment until day 28 after enrollment. Patients who die prior to day 28 after enrollment receive a value of 0 for RRT-free days. Patients who continue to receive RRT through day 28 after enrollment receive a value of 0 for RRT-free days. Patients who achieve RRT cessation, return to receiving RRT, and do not again achieve RRT cessation before day 28 after enrollment receive a value of 0 for RRT-free days. For patients who achieve RRT cessation, return to receiving RRT, and subsequently achieve cessation of RRT again prior to day 28 after enrollment, RRT-free days will be awarded based on the time of the final RRT treatment prior to day 28 after enrollment. Survivors who never receive RRT will be awarded 28 RRT-free days. | Between ICU admission and Day 28 | 
| Ventilator-Free Days | Ventilator-free days to day 28 (VFDs) will be defined as the number of days from the time of initiating unassisted breathing (breathing without support of the mechanical ventilator) until day 28 after enrollment. Patients who die prior to day 28 after enrollment will receive a value of 0 for VFDs. Patients who never achieve unassisted breathing prior to day 28 after enrollment will receive a value of 0 for VFDs. Patients who achieve unassisted breathing, returned to assisted breathing, and do not again achieve unassisted breathing before day 28 after enrollment will receive a value of 0 for VFDs. For patients who achieve unassisted breathing, return to assisted breathing, and subsequently achieve unassisted breathing again prior to day 28 after enrollment, VFDs will be awarded based on the time of the final initiation of unassisted breathing prior to day 28 after enrollment. Survivors who never experience assisted breathing will receive 28 VFDs. | Between ICU admission and Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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balanced crystalloid, crystalloid, isotonic, acetate, non-acetate, lactated Ringer's, Normosol