Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis
- Conditions
- Septic Shock
- Interventions
- Drug: Early VasopressorsOther: Early Fluids
- Registration Number
- NCT03434028
- Lead Sponsor
- Massachusetts General Hospital
- Brief Summary
Multicenter, prospective, phase 3 randomized non-blinded interventional trial of fluid treatment strategies in the first 24 hours for patients with sepsis-induced hypotension. The aim of the study is to determine the impact of a restrictive fluids strategy (vasopressors first followed by rescue fluids) as compared to a liberal fluid strategy (fluids first followed by rescue vasopressors) on 90-day in-hospital mortality in patients with sepsis-induced hypotension.
- Detailed Description
Primary Hypothesis: Restrictive (vs liberal) fluid treatment strategy during the first 24 hours of resuscitation for sepsis-induced hypotension will reduce 90-day in-hospital mortality.
1. We will emphasize early screening and protocol initiation, and enroll a maximum of 2320 patients with suspected sepsis-induced hypotension.
* All patients will receive at least 1 liter of fluids prior to meeting study inclusion criteria (and no more than 3 liters prior to randomization).
* Patients will be enrolled within 4 hours of meeting study inclusion criteria
* Any type of isotonic crystalloid (normal saline, ringers lactate, or a balanced solution such as plasmalyte) is permitted.
2. Restrictive Fluids (Early Vasopressors) Group
* Norepinephrine will be used as preferred vasopressor and titrated to achieve mean arterial pressure (MAP) between 65 mmHg and 75 mmHg
* "Rescue fluids" may be administered as 500ml boluses if predefined rescue criteria are met
3. Liberal Fluids (Fluids First)
* 2 liter infusion upon enrollment (may forego second liter if MAP/SBP and heart rate are normalized and clinical assessment if patient is fluid replete after the first liter).
* Administer 500ml fluid boluses for fluid triggers until 5 liters administered or development of clinical signs of acute volume overload develop
* "Rescue vasopressors" may be administered after 5 liters of fluid, for development of acute volume overload, or if other predefined rescue criteria are met
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1563
- Age ≥ 18 years
- A suspected or confirmed infection (broadly defined by administration or planned administration of antibiotics)
- Sepsis-induced hypotension defined as systolic blood pressure < 100 mmHg or MAP < 65 mmHg after a minimum of at least 1 liter of fluid (*Fluids inclusive of pre-hospital fluids; blood pressure must be below any known or reported pre-morbid baseline).
- More than 4 hours elapsed since meeting inclusion criteria or 24 hours elapsed since admission to the hospital
- Patient already received 3 liters of intravenous fluid (includes prehospital volumes)
- Unable to obtain informed consent
- Known pregnancy
- Hypotension suspected to be due to non-sepsis cause (e.g. hemorrhagic shock)
- Blood pressure is at known or reported baseline level
- Severe Volume Depletion from an acute condition other than sepsis. In the judgment of the treating physician, the patient has an acute condition other than sepsis causing (or indicative) of *severe volume depletion; Examples include: Diabetic ketoacidosis, high volume vomiting or diarrhea, hyperosmolar hyperglycemic state, and nonexertional hyperthermia (heat stroke); severe is defined by the need for substantial intravenous fluid administration as part of routine clinical care
- Pulmonary edema or clinical signs of new fluid overload (e.g. bilateral crackles, new oxygen requirement, new peripheral edema, fluid overload on chest x-ray)
- Treating physician unwilling to give additional fluids as directed by the liberal protocol
- Treating physician unwilling to use vasopressors as directed by the restrictive protocol.
- Current or imminent decision to withhold most/all life-sustaining treatment; this does not exclude those patients committed to full support except cardiopulmonary resuscitation
- Immediate surgical intervention planned such that study procedures could not be followed
- Prior enrollment in this study
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Restrictive Fluids Early Vasopressors The general approach will be to use vasopressors to treat hypotension as opposed to intravenous fluids. Maintenance fluids should not be used. Liberal Fluids Early Fluids The general approach is to use fluid boluses to treat hypotension.
- Primary Outcome Measures
Name Time Method Death Before Discharge Home by Day 90 From randomization to discharge home up to and including day 90. The primary outcome was death from any cause before discharge home by day 90. Point estimates were from Kaplan-Meier curves. There were 109 deaths and 5 patients with censored data the restrictive fluid group and 116 deaths and 4 patients with censored data in the liberal group. We defined home as the same setting or a setting similar to the one where the patient resided before becoming ill. Thus, if a patient originated from a private residence and was discharged from the hospital to a rehabilitation setting, we assessed for vital status until return to the private residence.Vital status was determined using any of the following methods: medical record review, phone calls to patient, proxy or healthcare facility, review of obituaries, or information from the Centers for Disease Control and Prevention's National Death Index (NDI).
- Secondary Outcome Measures
Name Time Method Vasopressor Free Days From study day 2 through day 28 The number of calendar days between day 2 (eligibility starting 48 hours post randomization) and 26 days later that the patient is alive and without the use of vasopressor therapy. Patients who died prior to day 28 are assigned zero vasopressor free days.
New Intubation With Invasive Mechanical Ventilation by 28 Days 28 days after randomization Patients who receive invasive mechanical ventilation via endotracheal or tracheostomy tube, except those intubated solely for a procedure and extubated within 24 hours, through to study day 28 meet this endpoint. Non-invasive mechanical ventilation will not be included as an outcome. This is a binary outcome.
Organ Support Free Days 28 days after randomization Defined as a patient being alive and without assisted breathing, new renal replacement therapy, or vasopressors (excluding vasopressor use prior to 48 hours). Any day that a patient is alive and without organ support will represent days alive and free of organ support.
Renal Replacement Free Days 28 days after randomization The number of calendar days between randomization and 28 days later that the patient is alive and without renal replacement therapy. Patients who died prior to day 28 are assigned zero renal replacement free days.
ICU Free Days 28 days after randomization Defined as the number of days spent alive out of the ICU to day 28.
Kidney Disease: Change in Creatinine-based Global Outcomes (KIDGO) Score Between Baseline and 72 Hours 72 hours after randomization Assessment of renal function using the KDIGO staging system (using serum creatinine criteria only) between baseline and 72 hours post randomization to assess for de novo acute kidney injury (AKI) (e.g., meeting criteria for AKI by KDIGO criteria) or worsening AKI (e.g., increasing severity). Patients on chronic renal replacement therapy were not eligible for this endpoint determination.
Scoring of 1-3 (using serum creatinine levels; a higher score indicates worsening kidney function):
1. creatinine level 1.5-1.9 times baseline OR \>/= 0.3 mg/dl (\>/= 25.5 umol/l) increase
2. creatinine level 2.0-2.9 times baseline
3. creatinine level 3.0 times baseline OR increase in serum creatinine to \>/=4.0mg/dl (\>/= 353 umol/l) OR initiation of renal replacement therapyHospital Free Days to Discharge Home 28 days after randomization Days alive post hospital discharge through day 28. Patients who die on or prior to day 28 are assigned zero hospital free days.
Death From Any Cause at Any Location by Day 90 From randomization to and including day 90 Subjects were contacted at day 90 to ascertain their survival status via telephone contact with the patient or family members or by a review of medical records and publicly available data sources.
Development of ARDS 7 days after randomization Presence and severity of ARDS is determined using the PaO2/FiO2 ratio or SpO2/FiO2 ratio and confirmation of ARDS through chest x-ray reviews.
Ventilator Free Days (VFD) 28 days after randomization Ventilator-free days is defined to be 28 days minus the duration of mechanical ventilation through day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days.
Initiation of Renal Replacement Therapy 28 days after randomization Patients receiving (new) renal replacement therapy through day 28. Patients with chronic renal replacement therapy initiated prior to the current sepsis illness were not eligible to meet this endpoint.
New Onset Atrial or Ventricular Arrhythmia 28 days after randomization The occurrence of one or more episodes (sustained for more than 1 minute for SVT and AF, \> 15 seconds for VT) during through day 28 will be recorded.
Change in SOFA (Sepsis Related Organ Failure Assessment) Score 72 hours after randomization SOFA score was calculated at enrollment and at 72 hours using clinically available data.Total score: 0-4 points; 4 = worst outcome. Values not available at baseline were assumed normal. 72 hours assessment: Closest previously known value was carried forward for missing values. SOFA Scoring Breakout (lower scores mean a better outcome; clinically significant organ failure for CLOVERS was defined as a SOFA score 2 or more points higher than baseline):
* Coagulation( Platelets, ×10³/µL): Score = 0: \>150; 1: \</= 150; 2: \</= 100; 3: \</= 50; 4: \</= 2
* Liver (Bilirubin, mg/dL): Score: 0: \<1.2; 1: 1.2-1.9; 2: 2.0-5.9; 3: 6.0-11.9; 4: \>11.9
* Cardiovascular(Hypotension): Score: 0: no hypotension; 1: Mean arterial pressure \<70 mmHg; 2: Dopamine\</=5 OR any dobutamine; 3: Dopanime \>5, epinephrine \</=0, or Norepi \</=0.1; 4: Dop \>15, epi \>0.1, or norepi \>0.1
* Renal (Creatinine, mg/dL or urine output, ml/d): Score: 0: \<1.2; 1: 1.2-1.9; 3: 2.0-3.4; 3: 3.5-4.9 or \<500; 4: \>4.9 or \<200
Trial Locations
- Locations (49)
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Ohio State University Wexner Medical Center
🇺🇸Columbus, Ohio, United States
Temple University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
UPMC Presbyterian
🇺🇸Pittsburgh, Pennsylvania, United States
Ronald Reagan UCLA
🇺🇸Los Angeles, California, United States
Indiana University Health Methodist Hospital
🇺🇸Indianapolis, Indiana, United States
University of Cincinnati Medical Center
🇺🇸Cincinnati, Ohio, United States
UCSF San Francisco
🇺🇸San Francisco, California, United States
Beth Israel Medical Center
🇺🇸Boston, Massachusetts, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Brigham and Women's Hospital
🇺🇸Boston, Massachusetts, United States
Hennepin County Medical Center
🇺🇸Minneapolis, Minnesota, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
University of Utah Health Sciences Center
🇺🇸Salt Lake City, Utah, United States
LDS Hospital
🇺🇸Salt Lake City, Utah, United States
Harborview Medical Center
🇺🇸Seattle, Washington, United States
University of Washington Medical Center
🇺🇸Seattle, Washington, United States
Swedish Hospital First Hill
🇺🇸Seattle, Washington, United States
University Medical Center (LSU)
🇺🇸New Orleans, Louisiana, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
University of Kentucky
🇺🇸Lexington, Kentucky, United States
Maine Medical Center
🇺🇸Portland, Maine, United States
University of Arizona
🇺🇸Tucson, Arizona, United States
Penn State Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
Denver Health Medical Center
🇺🇸Denver, Colorado, United States
St. Joseph Hospital
🇺🇸Denver, Colorado, United States
University of Colorado Hospital
🇺🇸Aurora, Colorado, United States
Oregon Health and Science University OHSU
🇺🇸Portland, Oregon, United States
Baystate Medical Center
🇺🇸Springfield, Massachusetts, United States
Stanford University Hospital
🇺🇸Stanford, California, United States
UCSF Fresno
🇺🇸Fresno, California, United States
Yale New Haven Hospital
🇺🇸New Haven, Connecticut, United States
St. Vincent Hospital
🇺🇸Worcester, Massachusetts, United States
University of Minnesota Medical Center
🇺🇸Minneapolis, Minnesota, United States
University of Michigan Medical Center
🇺🇸Ann Arbor, Michigan, United States
University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Mt. Sinai Hospital
🇺🇸New York, New York, United States
Wake Forest Baptist Health
🇺🇸Winston-Salem, North Carolina, United States
UPMC Mercy
🇺🇸Pittsburgh, Pennsylvania, United States
UPMC Shadyside
🇺🇸Pittsburgh, Pennsylvania, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Intermountain Medical Center
🇺🇸Murray, Utah, United States
University of Texas Health Science Center
🇺🇸Houston, Texas, United States
McKay-Dee Hospital
🇺🇸Ogden, Utah, United States
Utah Valley Regional Medical Center
🇺🇸Provo, Utah, United States
University Virginia Medical Center
🇺🇸Charlottesville, Virginia, United States
VCU Medical Center
🇺🇸Richmond, Virginia, United States
Montefiore Medical Center
🇺🇸New York, New York, United States