Restricted or Liberal Fluid for Haemodynamic Resuscitation in Sepsis (FRESHLY)

Fluid Restricted Resuscitation in Sepsis With Hypotension Meta-Analysis (FRESHLY): Individual Patient Data Met-analysis of the ARISE FLUIDS, CLASSIC, CLOVERS and EVIS Trials

A prospective, individual patient data meta-analysis (IPDMA) of four multicentre, open-label, randomised clinical trials of initial haemodynamic resuscitation in patients with septic shock.

Study Overview

• Status: Not yet recruiting
• Conditions: Septic Shock; Fluid Resuscitation
• Intervention / Treatment: Other: Vasopressors; Other: Fluids

Detailed Description

This study is a prospective, individual patient data meta-analysis (IPDMA) of four multicentre, open-label, randomised clinical trials of initial haemodynamic resuscitation in patients with septic shock.

The investigators will include four multicentre, open-label, randomised, clinical trials:

• Australasian Resuscitation in Sepsis Evaluation Fluids of Vasopressors in Emergency Department Sepsis (ARISE FLUIDS) trial conducted in Australia and New Zealand. ClinicalTrials.gov identifier NCT04569942
• Conservative versus Liberal Approach to fluid therapy of Septic Shock in intensive Care (CLASSIC) trial conducted in seven European countries. ClinicalTrials.gov identifier NCT03668236
• Crystalloid Liberal or Vasopressors Early (CLOVERS) trial conducted in the United States. ClinicalTrials.gov identifier NCT03434028
• Early Vasopressors in Sepsis (EVIS) trial conducted in the United Kingdom. ClinicalTrials.gov identifier NCT05179499

All four trials have all received relevant approval from a research ethics committee with a locally appropriate method of obtaining consent. These trials are prospectively chosen prior to the results of any individual trial being known because they are investigating the same broad question in patients with acute septic shock across several countries. The investigators of these trials collaborated to harmonise data and outcomes as far as possible across all trials to facilitate an IPDMA.

The aims to provide high level evidence to address the question of whether a fluid sparing/early vasopressor approach or a liberal fluid/later vasopressor approach to initial haemodynamic resuscitation in septic shock results in improved outcomes, including mortality.

• Study Type: Observational
• Enrollment (Estimated): 7838

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

All trials include adult patients requiring resuscitation for hypotension or hypoperfusion due to suspected sepsis as defined in the original studies. Participants may be enrolled in the emergency department, acute care ward or intensive care unit.

Description

Inclusion Criteria:

Participants of the ARISE FLUIDS, CLASSIC, CLOVERS & EVIS trials who had:

• Suspected or proven infection
• Systolic blood pressure (SBP) <100 mm Hg OR mean arterial pressure (MAP) <65 mm Hg
• Lactate ≥ 2.0 mmol/L
• Requirement for vasopressors to meet perfusion targets

Exclusion criteria:

Participants not in the ARISE FLUIDS, CLASSIC, CLOVERS & EVIS trials

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Other

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Vasopressors; A haemodynamic resuscitation strategy based upon the restriction of IV fluids (by either volume or rate of infusion) with initiation or change of rate of vasopressors if required to meet perfusion targets	Other: Vasopressors; A haemodynamic resuscitation strategy based upon the restriction of IV fluids (by either volume or rate of infusion) with initiation or change of rate of vasopressors if required to meet perfusion targets
Fluids; A strategy of resuscitation with intravenous fluids as the primary intervention to achieve perfusion targets with subsequent initiation or change of rate of vasopressors if required.	Other: Fluids; A strategy of resuscitation with intravenous fluids as the primary intervention to achieve perfusion targets with subsequent initiation or change of rate of vasopressors if required.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality at 90 days post randomisation	Death from any cause at 90 days after randomisation	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time from randomisation to death	Time from randomisation to death	Up to day 90
Incidence of mechanical ventilation	Commencement of mechanical ventilation from randomisation until day 90 post-randomisation	from randomisation until day 90 post-randomisation
Incidence of acute renal replacement therapy	Commencement of renal replacement therapy from randomisation until day 90 post-randomisation	from randomisation until day 90 post-randomisation
Days alive free of organ support at 28 days post randomisation	days the patient is alive and receiving nil organ support from from randomisation until day 28 post-randomisation	from randomisation until day 28 post-randomisation
Duration of hospital stay	Length of time in hospital from randomisation until death or hospital discharge or day 90 post-randomisation	From randomisation until day 90 post-randomisation
Incidence of serious adverse events	Number of adverse events from randomisation until day 90 post-randomisation	from randomisation until day 90 post-randomisation
Duration of intensive care unit (ICU) stay	Length of time in ICU from randomisation until death or hospital discharge or day 90 post-randomisation	From randomisation until day 90 post-randomisation

Collaborators and Investigators

• Sponsor: Australian and New Zealand Intensive Care Research Centre

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2025
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: June 3, 2022
• First Submitted That Met QC Criteria: July 7, 2022
• First Posted (Actual): July 12, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 1, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Shock, Septic; Vasoconstrictor Agents
• Other Study ID Numbers: FRESHLY V1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No