Clinical trial NCT03434028: Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis
Official title: Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Septic Shock
Keywords: Fluid management
Sepsis-induced hypotension
vasopressors
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
First posted: 2018-02-15
Enrollment: 1563
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: Inclusion Criteria:

* 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).

Exclusion Criteria:

* 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

Primary outcomes:
measure: Death Before Discharge Home by Day 90
timeFrame: From randomization to discharge home up to and including day 90.
Secondary outcomes:
measure: Organ Support Free Days
timeFrame: 28 days after randomization
measure: Ventilator Free Days (VFD)
timeFrame: 28 days after randomization
measure: Renal Replacement Free Days
timeFrame: 28 days after randomization
measure: Vasopressor Free Days
timeFrame: From study day 2 through day 28
measure: ICU Free Days
timeFrame: 28 days after randomization
measure: Hospital Free Days to Discharge Home
timeFrame: 28 days after randomization
measure: New Intubation With Invasive Mechanical Ventilation by 28 Days
timeFrame: 28 days after randomization
measure: Initiation of Renal Replacement Therapy
timeFrame: 28 days after randomization
measure: Kidney Disease: Change in Creatinine-based Global Outcomes (KIDGO) Score Between Baseline and 72 Hours
timeFrame: 72 hours after randomization
measure: Change in SOFA (Sepsis Related Organ Failure Assessment) Score
timeFrame: 72 hours after randomization
measure: Development of ARDS
timeFrame: 7 days after randomization
measure: New Onset Atrial or Ventricular Arrhythmia
timeFrame: 28 days after randomization
measure: Death From Any Cause at Any Location by Day 90
timeFrame: From randomization to and including day 90
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Fresno
country: United States
facility: UCSF Fresno
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA
state: California
city: San Francisco
country: United States
facility: UCSF San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University Hospital
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Denver
country: United States
facility: Denver Health Medical Center
state: Colorado
city: Denver
country: United States
facility: St. Joseph Hospital
state: Colorado
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Indianapolis
country: United States
facility: Indiana University Health Methodist Hospital
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: New Orleans
country: United States
facility: University Medical Center (LSU)
state: Louisiana
city: Portland
country: United States
facility: Maine Medical Center
state: Maine
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: St. Vincent Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center
state: Minnesota
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: New York
country: United States
facility: Mt. Sinai Hospital
state: New York
city: New York
country: United States
facility: Montefiore Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University OHSU
state: Oregon
city: Hershey
country: United States
facility: Penn State Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Mercy
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Shadyside
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Ogden
country: United States
facility: McKay-Dee Hospital
state: Utah
city: Provo
country: United States
facility: Utah Valley Regional Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Health Sciences Center
state: Utah
city: Salt Lake City
country: United States
facility: LDS Hospital
state: Utah
city: Charlottesville
country: United States
facility: University Virginia Medical Center
state: Virginia
city: Richmond
country: United States
facility: VCU Medical Center
state: Virginia
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Seattle
country: United States
facility: Swedish Hospital First Hill
state: Washington
Study officials:
affiliation: Massachusetts General Hospital
name: David Alan Schoenfeld, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Self WH, Semler MW, Bellomo R, Brown SM, deBoisblanc BP, Exline MC, Ginde AA, Grissom CK, Janz DR, Jones AE, Liu KD, Macdonald SPJ, Miller CD, Park PK, Reineck LA, Rice TW, Steingrub JS, Talmor D, Yealy DM, Douglas IS, Shapiro NI; CLOVERS Protocol Committee and NHLBI Prevention and Early Treatment of Acute Lung Injury (PETAL) Network Investigators. Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial. Ann Emerg Med. 2018 Oct;72(4):457-466. doi: 10.1016/j.annemergmed.2018.03.039. Epub 2018 May 10.