Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS)

Mass General Brigham

Status and phase: Completed; Phase 3

Conditions: Septic Shock

Treatments: Drug: Early Vasopressors; Other: Early Fluids

Study type: Interventional

Funder types: Other

Identifiers

NCT03434028

PETAL03 CLOVERS

Details and patient eligibility

About

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.

Full 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

Enrollment: 1,563 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,563 participants in 2 patient groups

Restrictive Fluids

Other group

Description:

The general approach will be to use vasopressors to treat hypotension as opposed to intravenous fluids. Maintenance fluids should not be used.

Treatment:

Drug: Early Vasopressors

Liberal Fluids

Other group

Description:

The general approach is to use fluid boluses to treat hypotension.

Treatment:

Other: Early Fluids