Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis
NCT ID: NCT03434028
Last Updated: 2023-07-06
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
1563 participants
INTERVENTIONAL
2018-03-07
2022-08-24
Brief Summary
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Detailed Description
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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
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Restrictive Fluids
The general approach will be to use vasopressors to treat hypotension as opposed to intravenous fluids. Maintenance fluids should not be used.
Early Vasopressors
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.
Liberal Fluids
The general approach is to use fluid boluses to treat hypotension.
Early Fluids
Additional 2 liter intravenous fluid 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. Any type of isotonic crystalloid (normal saline, ringers lactate, balanced solution such as plasmalyte) is permitted.
Interventions
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Early Vasopressors
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.
Early Fluids
Additional 2 liter intravenous fluid 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. Any type of isotonic crystalloid (normal saline, ringers lactate, balanced solution such as plasmalyte) is permitted.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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).
* 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
18 Years
ALL
No
Sponsors
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Massachusetts General Hospital
OTHER
Responsible Party
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Boyd Taylor Thompson
PETAL CCC Prinicipal Investigator
Principal Investigators
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David Alan Schoenfeld, PhD
Role: PRINCIPAL_INVESTIGATOR
Massachusetts General Hospital
Locations
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University of Arizona
Tucson, Arizona, United States
UCSF Fresno
Fresno, California, United States
Ronald Reagan UCLA
Los Angeles, California, United States
UCSF San Francisco
San Francisco, California, United States
Stanford University Hospital
Stanford, California, United States
University of Colorado Hospital
Aurora, Colorado, United States
Denver Health Medical Center
Denver, Colorado, United States
St. Joseph Hospital
Denver, Colorado, United States
Yale New Haven Hospital
New Haven, Connecticut, United States
Indiana University Health Methodist Hospital
Indianapolis, Indiana, United States
University of Kentucky
Lexington, Kentucky, United States
University Medical Center (LSU)
New Orleans, Louisiana, United States
Maine Medical Center
Portland, Maine, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Brigham and Women's Hospital
Boston, Massachusetts, United States
Beth Israel Medical Center
Boston, Massachusetts, United States
Brigham and Women's Hospital
Boston, Massachusetts, United States
Baystate Medical Center
Springfield, Massachusetts, United States
St. Vincent Hospital
Worcester, Massachusetts, United States
University of Michigan Medical Center
Ann Arbor, Michigan, United States
University of Minnesota Medical Center
Minneapolis, Minnesota, United States
Hennepin County Medical Center
Minneapolis, Minnesota, United States
University of Mississippi Medical Center
Jackson, Mississippi, United States
Mt. Sinai Hospital
New York, New York, United States
Montefiore Medical Center
New York, New York, United States
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
Duke University Medical Center
Durham, North Carolina, United States
Wake Forest Baptist Health
Winston-Salem, North Carolina, United States
University of Cincinnati Medical Center
Cincinnati, Ohio, United States
Cleveland Clinic Foundation
Cleveland, Ohio, United States
Ohio State University Wexner Medical Center
Columbus, Ohio, United States
Oregon Health and Science University OHSU
Portland, Oregon, United States
Penn State Hershey Medical Center
Hershey, Pennsylvania, United States
Temple University Hospital
Philadelphia, Pennsylvania, United States
UPMC Mercy
Pittsburgh, Pennsylvania, United States
UPMC Presbyterian
Pittsburgh, Pennsylvania, United States
UPMC Shadyside
Pittsburgh, Pennsylvania, United States
Medical University of South Carolina
Charleston, South Carolina, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
University of Texas Health Science Center
Houston, Texas, United States
Intermountain Medical Center
Murray, Utah, United States
McKay-Dee Hospital
Ogden, Utah, United States
Utah Valley Regional Medical Center
Provo, Utah, United States
University of Utah Health Sciences Center
Salt Lake City, Utah, United States
LDS Hospital
Salt Lake City, Utah, United States
University Virginia Medical Center
Charlottesville, Virginia, United States
VCU Medical Center
Richmond, Virginia, 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
Countries
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References
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Oshima K, Di Gravio C, Yan B, McMurtry SA, Burke R, Levoir LM, Kravitz MS, Stephenson D, Issaian A, Hansen KC, D'Alessandro A, Douglas IS, Self WH, Lindsell CJ, Schildcrout JS, Schmidt EP, Shapiro NI. Endothelial Glycocalyx Degradation in Sepsis: Analysis of the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) Trial, a Multicenter, Phase 3, Randomized Trial. Ann Am Thorac Soc. 2025 Sep;22(9):1382-1393. doi: 10.1513/AnnalsATS.202501-012OC.
Jorda A, Douglas IS, Staudinger T, Heinz G, Bergmann F, Oberbauer R, Sengolge G, Zeitlinger M, Jilma B, Shapiro NI, Gelbenegger G. Fluid management for sepsis-induced hypotension in patients with advanced chronic kidney disease: a secondary analysis of the CLOVERS trial. Crit Care. 2024 Jul 11;28(1):231. doi: 10.1186/s13054-024-05019-6.
National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network; Shapiro NI, Douglas IS, Brower RG, Brown SM, Exline MC, Ginde AA, Gong MN, Grissom CK, Hayden D, Hough CL, Huang W, Iwashyna TJ, Jones AE, Khan A, Lai P, Liu KD, Miller CD, Oldmixon K, Park PK, Rice TW, Ringwood N, Semler MW, Steingrub JS, Talmor D, Thompson BT, Yealy DM, Self WH. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med. 2023 Feb 9;388(6):499-510. doi: 10.1056/NEJMoa2212663. Epub 2023 Jan 21.
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.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Document Type: Informed Consent Form
Other Identifiers
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PETAL03 CLOVERS
Identifier Type: -
Identifier Source: org_study_id
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