Restrictive Fluid Administration vs. Standard of Care in Emergency Department Sepsis Patients

Study Overview
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Brief Summary
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This is an investigator-initiated, multicenter, randomized, parallel-group, open-labeled, feasibility trial investigating volumes of fluid within 24 hours in 124 patients with sepsis allocated to two different IV fluid regimens enrolled at three emergency departments in Central Region Denmark. The primary outcome is total intravenous, crystalloid fluid volume within 24 hours and key secondary outcomes include protocol violations, total fluids (intravenous and oral) within 24 hours, SAEs/SUSARs, and inhospital-, 30- and 90-day mortality.

Detailed Description
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BACKGROUND: Sepsis is common in emergency department (ED) patients. Traditionally, intravenous (IV) fluids are used to optimise the circulation, and the use of higher volumes is recommended by international guidelines, but there are no recommendations for sepsis without hypotension or shock. Studies in septic shock seem to favour fluid restriction. Whether this is true in sepsis without hypotension/shock is unknown. OBJECTIVES: The aim of the REFACED Sepsis trial is to test if an IV fluid restrictive protocol in ED patients with sepsis is feasible, i.e., if the protocol decreases the IV fluid volumes administered. DESIGN: REFACED Sepsis is a multicenter, randomized, parallel-group, open-labeled, feasibility trial POPULATION: ED patients with sepsis expected to be admitted for ≥ 24 hours EXPERIMENTAL INTERVENTION: In the IV fluid restriction group no IV fluids should be given unless one of the below mentioned occurs; A fluid bolus of 250 ml isotonic crystalloid may be given within 15 minutes if one of the following occurs (hypoperfusion criteria): Lactate concentration ≥ 4 mmol/l (arterial or venous blood gas/blood sample) Hypotension (systolic BP < 90 mmHg) Mottling beyond edge of kneecap (i.e., Mottling score >2)53 Severe oliguria, i.e., diuresis < 0.1 ml/kg/h, during the first 4 hours of admission All patients will be ensured min. 1 L of oral/intravenous fluids in 24 hours and electrolytes can be corrected. CONTROL INTERVENTION: In the usual care group there will be no upper limit for the use of IV fluids. OUTCOMES: The primary outcome is 24-hour intravenous crystalloid fluid administration. Key secondary outcomes are: Feasibility measures: Number of patients with major protocol violations, Number of patients screened vs included, Time from admission to inclusion, Number of patients lost to follow up in terms of 24-hour fluids, Accumulated serious adverse reactions and events (SAEs + Suspected Unexpected Serious Adverse Reaction (SUSARs)) within 48 hours in-hospital, Total fluids (oral and intravenous) at 24 hours, TRIAL-SIZE: 124 patients will be randomized to restrictive fluid administration or usual care within 24 hours of randomization

Official Title
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Restrictive Fluid Administration vs. Standard of Care in Emergency Department Sepsis Patients - a Multicenter, Randomized Clinical Feasibility Trial (REFACED Sepsis)

Conditions
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Sepsis

Intervention / Treatment
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* Drug: Isotonic crystalloids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All of the below must be fulfilled: Unplanned emergency department admission Age ≥ 18 years Sepsis defined as suspected infection by the treating clinician AND blood cultures drawn AND IV antibiotics administered or planned AND An infection related increase of SOFA*-score ≥ 2 from baseline Expected hospital stay > 24 hours as deemed by treating clinician Sequential Organ Failure Assessment (SOFA) Score Further more the patient must fulfill criteria for enrollment in an acute study according to Danish law Exclusion Criteria: We will exclude patients fulfilling any of following exclusion criteria: ≥ 500 ml of fluids given prior to randomization Invasively ventilated or vasopressors initiated at the time of screening Known or suspected severe bleeding judged by the treating clinician Known or suspected pregnancy (women aged <45 years will have a pregnancy test performed before enrollment) Prior enrollment in the trial Patients, who the clinician expect not to survive the next 24-hours

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Restrictive fluid administration<br>No IV fluids unless one of the extenuating circumstances occur; In case of severe hypoperfusion or severe circulatory impairment defined by either: 1) Lactate≥4 mmol/L, 2) Hypotension (systolic BP < 90 mmHg), 3) Mottling beyond the kneecap (mottling score >2) OR 4) Urinary output<0.1 mL/kg bodyweight/h (only in the first 4hrs after randomization) then a bolus of 250 ml of IV crystalloid solution may be given followed by re-evaluation In case of overt fluid losses (e.g. vomiting, large aspirates,) IV fluid may be given to correct for the loss, but not above the volume lost. In case the oral/enteral route for water or electrolyte solutions is contraindicated or has failed, IV fluids may be given to: Correct dehydration or electrolyte deficiencies Ensure a total fluid input of 1 L in 24hrs IV fluids may be given as carrier for medication, but with lowest possible volume | Drug: Isotonic crystalloids<br>* Types of fluids in both intervention groups: Fluids used for electrolyte disturbances: Fluids should be chosen to substitute the specific deficiency Fluids given to substitute overt loss: Isotonic crystalloids are to be used. If large amounts of ascites are tapped, then human albumin may be used. Blood products are only to be used on specific indications including severe bleeding, severe anaemia and prophylactic in case of severe coagulopathy.<br>|
| Active Comparator: Usual care (standard care)<br>There will be no upper limit for the use of either IV or oral/enteral fluids IV fluids should be given in the case of hypoperfusion or circulatory impairment and should be continued as long as hemodynamic variables improve including static or dynamic variable(s) as chosen by the clinicians. These criteria are based on the Surviving Sepsis Campaign guideline. IV fluids should be given as maintenance if the ICU has a protocol recommending maintenance fluid IV fluids should be given to substitute expected or observed loss, dehydration or electrolyte derangements | Drug: Isotonic crystalloids<br>* Types of fluids in both intervention groups: Fluids used for electrolyte disturbances: Fluids should be chosen to substitute the specific deficiency Fluids given to substitute overt loss: Isotonic crystalloids are to be used. If large amounts of ascites are tapped, then human albumin may be used. Blood products are only to be used on specific indications including severe bleeding, severe anaemia and prophylactic in case of severe coagulopathy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-hour crystalloid iv. fluids | total amount of all administered intravenous, crystalloid fluids within 24 hours of randomization | 24 hours from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Protocol violations | Feasibility measure: Number of patients with major protocol violations | 24 hours from randomization | 
| Screened-vs.-randomized-ratio | Feasibility measure: Number of patients screened vs included | Through study completion, an average of 1 year | 
| Time to inclusion | Feasibility measure: Time from admission to inclusion/randomization (hours) | Through study completion, an average of 1 year | 
| Lost-to-follow-up-rate | Feasibility measure: Number of patients lost to follow up in terms of 24-hour fluids | 24 hours from randomization | 
| Accumulated serious adverse reactions (SARs + SUSARs) | Feasibility measure: Accumulated serious adverse reactions and events (SAEs + SARs+ SUSARs) within 7 days in-hospital | 7 days from randomization | 
| Total 24-hour fluids | Total fluids (oral and intravenous) at 24 hours | 24 hours from randomization | 
| Mortality | In-hospital, 30- and 90-days mortality | Total of 90-days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sepsis, Hypotension, IV fluid therapy, Fluid resuscitation, Emergency Department, Crystalloids