Restricted or Liberal Fluid for Haemodynamic Resuscitation in Sepsis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Septic Shock, Fluid Resuscitation

Intervention / Treatment
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* Other: Vasopressors
* Other: Fluids


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Vasopressors<br>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<br>* 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<br>|
| Fluids<br>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<br>* 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.<br>|

What is the study measuring?
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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 |