A Randomized Controlled Trial of a Conservative Fluid Balance Strategy for Patients With Sepsis and Cardiopulmonary Dysfunction (BALANCE Study) (BALANCE)

A Phase II/III Randomized Controlled Trial of a Conservative Fluid Balance Strategy for Patients With Sepsis and Cardiopulmonary Dysfunction

Sepsis is a common inflammatory response to infection characterized by hypovolemia and vasodilation for which early administration of intravenous fluids has been suggested to improve outcomes. The ideal fluid balance following initial resuscitation is unclear. Septic patients treated in the intensive care unit commonly receive significant volumes of intravenous fluids with resultant positive fluid balance for up to a week after their initial resuscitation. Observational studies have associated fluid receipt and positive fluid balance in patients with severe sepsis and septic shock with increased mortality but are inherently limited by indication bias. In order to determine the optimal approach to fluid management following resuscitation in patients with severe sepsis and septic shock, a randomized controlled trial is needed. The primary hypothesis of this study is that, compared to usual care, a conservative approach to fluid management after resuscitation in patients with sepsis and cardiopulmonary dysfunction will increase intensive care unit free days.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Other: Conservative Fluid Management Strategy

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• ICU patients
• Adults
• Sepsis as defined by at least two systemic inflammatory response syndrome criteria and receipt of antimicrobial therapy
• Cardiopulmonary dysfunction as defined shock or respiratory failure

Exclusion Criteria:

• Inability to obtain consent
• Greater than 48 hours since inclusion criteria initially met
• Allergy to furosemide AND bumetanide
• Rhabdomyolysis with creatinine kinase > 5000 U/L
• Hypercalcemia with calcium >11 mg/dL
• Diabetic Ketoacidosis requiring continuous insulin infusion
• Tumor Lysis Syndrome diagnosed clinically
• Pancreatitis diagnosed clinically
• Chronic Hypoxic Respiratory Failure with Home Oxygen Use of FiO2≥0.3
• Chronic ventilator dependence
• cervical spinal cord injury at level C5 or higher
• amyotrophic lateral sclerosis
• Guillain-Barré Syndrome
• myasthenia gravis
• Renal failure requiring renal replacement therapy
• Burns >20% of body surface area
• Pregnant
• Preexisting pulmonary hypertension with PAPmean>40 on RHC
• Severe chronic liver disease with Childs-Pugh Score >11
• Moribund and not expected to survive an additional 24 hours
• Actively withdrawing life support or transitioning to comfort measures only
• Unwillingness of treating physician to employ conservative fluid strategy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Usual Care; Patients in the usual care arm will be managed exclusively by their treating clinician without input from study personnel.
Experimental: Conservative Fluid Management Strategy; For patients in the conservative fluid management arm, beginning 12 hours after admission to study ICU and ending at the first of ICU discharge, death, return to home inspired oxygen, or study day 14, fluid management will be controlled by a study protocol. Patients in shock will receive fluid boluses only as specified by the protocol for oliguria and rapidly increasing vasopressor requirement. Patients not in shock will receive fluid boluses only as specified by the protocol for oliguria. Output will exceed input each day using a diuretic drip if required. Study protocol will be held only for pre-specified Safety Endpoints of persistent oliguria, decompensating shock, diuretic side effect, and intervening acute event.	Other: Conservative Fluid Management Strategy; For patients in the conservative fluid management arm, beginning 12 hours after admission to study ICU and ending at the first of ICU discharge, death, return to home inspired oxygen, or study day 14, fluid management will be controlled by a study protocol. Patients in shock will receive fluid boluses only as specified by the protocol for oliguria and rapidly increasing vasopressor requirement. Patients not in shock will receive fluid boluses only as specified by the protocol for oliguria. Output will exceed input each day using a diuretic drip if required. Study protocol will be held only for pre-specified Safety Endpoints of persistent oliguria, decompensating shock, diuretic side effect, and intervening acute event.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ICU-free Days to 14 Days After Enrollment	The primary outcome will be the number of ICU-free days to day 14 (defined as the number days alive and outside of the intensive care unit in the first 14 days after enrollment).	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventilator-free Days to Day 14	A secondary outcome will be the number of ventilator-free days (defined as the number of days alive and breathing unassisted after the final achievement of unassisted breathing before day 14)	14 days
In-hospital Mortality to Day 14	A secondary outcome will be in-hospital mortality to day 14 (defined as the incidence of mortality prior to hospital discharge within 14 days after enrollment).	14 days
Renal Replacement Therapy-free Days to Day 14	Renal replacement therapy-free days to day 14 (defined as the number of days alive and free of renal replacement therapy from the last receipt of renal replacement therapy after enrollment to study day 14)	14 days
Highest Stage of Acute Kidney Injury	Highest stage of acute kidney injury as defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria Stage 0 (no acute kidney injury) Stage 1 Serum creatinine 1.5-1.9 times baseline or ≥0.3 mg/dl (≥26.5 mmol/l) increase or Urine output <0.5 ml/kg/h for 6-12 hours Stage 2 Serum creatinine 2.0-2.9 times baseline or <0.5 ml/kg/h for ≥12 hours Stage 3 Serum creatinine 3.0 times baseline or Increase in serum creatinine to ≥4.0 mg/dl (≥353.6 mmol/l) or Initiation of renal replacement therapy or in patients <18 years, decrease in eGFR to <35 ml/min per 1.73 m² or Urine output <0.3 ml/kg/h for ≥24 hours or anuria for ≥12 hours	28 days
Highest Plasma Creatinine Between Enrollment and 28 Days After Enrollment	Highest plasma creatinine (mg/dL) between enrollment and 28 days after enrollment, censored at hospital discharge	28 days
Receipt of Renal Replacement Therapy	receipt of renal replacement therapy between enrollment and the first of 28 days or hospital discharge	28 days

Collaborators and Investigators

• Sponsor: Vanderbilt University
• Investigators: Principal Investigator: Matthew W. Semler, M.D., Vanderbilt University

Publications and helpful links

General Publications

• Semler MW, Janz DR, Casey JD, Self WH, Rice TW. Conservative Fluid Management After Sepsis Resuscitation: A Pilot Randomized Trial. J Intensive Care Med. 2020 Dec;35(12):1374-1382. doi: 10.1177/0885066618823183. Epub 2019 Jan 10.

Study record dates

Study Major Dates

• Study Start: July 1, 2014
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: June 3, 2014
• First Submitted That Met QC Criteria: June 5, 2014
• First Posted (Estimate): June 9, 2014

Study Record Updates

• Last Update Posted (Actual): November 1, 2019
• Last Update Submitted That Met QC Criteria: October 7, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Septic Shock; Sepsis; Severe Sepsis; Conservative Fluid Management; Fluid Balance; Fluid Restriction
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia
• Other Study ID Numbers: 140582

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No