Sepsis
Conditions
Keywords
Sepsis, Severe Sepsis, Septic Shock, Conservative Fluid Management, Fluid Balance, Fluid Restriction
Brief summary
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.
Interventions
OTHERConservative 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.
Sponsors
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ICU-free Days to 14 Days After Enrollment | 14 days | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Highest Plasma Creatinine Between Enrollment and 28 Days After Enrollment | 28 days | Highest plasma creatinine (mg/dL) between enrollment and 28 days after enrollment, censored at hospital discharge |
| Ventilator-free Days to Day 14 | 14 days | 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) |
| Receipt of Renal Replacement Therapy | 28 days | receipt of renal replacement therapy between enrollment and the first of 28 days or hospital discharge |
| Renal Replacement Therapy-free Days to Day 14 | 14 days | 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) |
| Highest Stage of Acute Kidney Injury | 28 days | 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 |
| In-hospital Mortality to Day 14 | 14 days | 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Usual Care Patients in the usual care arm will be managed exclusively by their treating clinician without input from study personnel. | 15 |
| 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. | 15 |
| Total | 30 |
Baseline characteristics
| Characteristic | Conservative Fluid Management Strategy | Total | Usual Care |
|---|---|---|---|
| Age, Continuous | 61 years | 63 years | 65 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 14 Participants | 28 Participants | 14 Participants |
| Sex: Female, Male Female | 8 Participants | 15 Participants | 7 Participants |
| Sex: Female, Male Male | 7 Participants | 15 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 15 | 3 / 15 |
| other Total, other adverse events | 0 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 |
Outcome results
Primary
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).
Time frame: 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Usual Care | ICU-free Days to 14 Days After Enrollment | 9 days |
| Conservative Fluid Management Strategy | ICU-free Days to 14 Days After Enrollment | 11 days |
Secondary
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
Time frame: 28 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Usual Care | Highest Plasma Creatinine Between Enrollment and 28 Days After Enrollment | 2.3 mg/dL |
| Conservative Fluid Management Strategy | Highest Plasma Creatinine Between Enrollment and 28 Days After Enrollment | 1.3 mg/dL |
Secondary
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
Time frame: 28 days
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Usual Care | Highest Stage of Acute Kidney Injury | No acute kidney injury | 5 Participants |
| Usual Care | Highest Stage of Acute Kidney Injury | Stage I | 0 Participants |
| Usual Care | Highest Stage of Acute Kidney Injury | Stage II | 4 Participants |
| Usual Care | Highest Stage of Acute Kidney Injury | Stage III | 6 Participants |
| Conservative Fluid Management Strategy | Highest Stage of Acute Kidney Injury | Stage III | 3 Participants |
| Conservative Fluid Management Strategy | Highest Stage of Acute Kidney Injury | No acute kidney injury | 6 Participants |
| Conservative Fluid Management Strategy | Highest Stage of Acute Kidney Injury | Stage II | 3 Participants |
| Conservative Fluid Management Strategy | Highest Stage of Acute Kidney Injury | Stage I | 2 Participants |
Secondary
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).
Time frame: 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care | In-hospital Mortality to Day 14 | 4 Participants |
| Conservative Fluid Management Strategy | In-hospital Mortality to Day 14 | 3 Participants |
Secondary
Receipt of Renal Replacement Therapy
receipt of renal replacement therapy between enrollment and the first of 28 days or hospital discharge
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care | Receipt of Renal Replacement Therapy | 1 Participants |
| Conservative Fluid Management Strategy | Receipt of Renal Replacement Therapy | 1 Participants |
Secondary
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)
Time frame: 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Usual Care | Renal Replacement Therapy-free Days to Day 14 | 14 days |
| Conservative Fluid Management Strategy | Renal Replacement Therapy-free Days to Day 14 | 14 days |
Secondary
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)
Time frame: 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Usual Care | Ventilator-free Days to Day 14 | 13 days |
| Conservative Fluid Management Strategy | Ventilator-free Days to Day 14 | 12 days |