Protocolised Early De-Resuscitation in Septic Shock (REDUCE)

Study Overview
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Brief Summary
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Background: Recent studies have questioned the safety of current fluid resuscitation strategies in patients with septic shock as prospective and observational data suggesting that the resulting fluid overload is associated with mortality. Two strategies have evolved to prevent or minimize fluid overload: restrictive fluid administration or active removal of accumulated fluid. While several small trials show benefits with a restrictive fluid administration regimen, active protocolized de-resuscitation was scarcely evaluated. The combination of both strategies yet warrants systematic evaluation. Aim: This study aims to assess the efficacy and feasibility of an early active de-resuscitation protocol in patients with septic shock. We hypothesize that the application of a structured early de-resuscitation protocol versus standard of care will lead to less fluid overload at day three after ICU admission. Study Intervention: Patients admitted to the ICU with confirmed or suspected septic shock (Sepsis-3 definition) will be randomized (1:1) to either the intervention or standard of care. In the intervention arm, patients are managed according to the REDUCE fluid management protocol during resuscitation and de-resuscitation.

Official Title
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Protocolised Early De-Resuscitation in Septic Shock (REDUCE) - a Randomised Controlled Multi-centre Feasibility Study

Conditions
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Septic Shock

Intervention / Treatment
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* Other: Fluid management according to the REDUCE Fluid Protocol
* Other: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients admitted to ICU with the diagnosis of septic shock as defined according to the Sepsis-3 criteria (suspected or confirmed infection AND vasopressor/inotrope ongoing to maintain MAP ≥ 65 mmHg AND Lactate ≥ 2 mmol/l in the last 6 hours Exclusion Criteria: Age <18 years Septic shock for more than 12 hours at the time of screening Acute burn injury >/= 10% of the body surface area Known pregnancy or lactating women Consent not obtainable due to national legislation Patients on chronic dialysis Patients that are known to be allergic to furosemide or metolazone

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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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized to receive either fluid resuscitation/de-resuscitation according to the REDUCE protocol or standard of care.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention: REDUCE Protocol<br>Fluid resuscitation and de-resuscitation is based on the REDUCE fluid management protocol. | Other: Fluid management according to the REDUCE Fluid Protocol<br>* Fluid management according to the protocol will be guided by pre-defined clinical signs for impaired perfusion and fluid overload.<br>* Other names: REDUCE protocol;|
| Active Comparator: Standard of Care<br>Fluid resuscitation and de-resuscitation according to the standard of care | Other: Standard of care<br>* Fluid resuscitation and de-resuscitation will be managed according to the standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patient with a negative fluid balance on day 3 | Proportion of patients with a negative cumulative fluid balance on day 3 | Up to day 3 after ICU admission | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with fluid overload at day 3 and ICU discharge | Fluid overload as defined as ((input-output)/admission weight)*100 | From hospital admission to the end of ICU stay, on average after 7 days | 
| Feasibility of the REDUCE fluid protocol | Number of REDUCE fluid protocol violations | From randomisation until the end of ICU stay, on average after 7 days | 
| Incidence of ischemic events and severe AKI | Number of patients with:ischaemic events, severe AKI (AKIN stage 2 or more); respectively episodes of: severe hypernatremia (sodium >/= 155mmol/l), severe hypokalemia (< 3.0 mmol/l), severe metabolic alkalosis (pH >/= 7.55, bicarbonate >/= 35 mmol/l), anaphylactic reaction to diuretic drug | Ischemic events and AKI: From randomisation until the end of ICU stay (on average after 7 days), and at day 30; electrolyte and acid-base/medication associated safety endpoints: during ICU stay (on average 7 days) | 
| Ventilator-free days at day 30 | Ventilator free days up to day 30 | Up to 30 days after randomisation | 
| Vasopressor-free days at day 30 | Vasopressor free days up to day 30 | Up to 30 days after randomisation | 
| Renal replacement therapy | Need for and time on renal replacement therapy | Up to 90 days after randomisation | 
| Number of patients with need for renal replacement at 90days | Number of patients with on-going need for renal replacement at 90days | Up to 90 days after randomisation | 
| All-cause mortality | At 30days and 90 days after randomization | Up to 90 days after randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Septic shock, Fluid resuscitation