Clinical trial NCT05076435: Restrictive Fluid Administration vs. Standard of Care in Emergency Department Sepsis Patients
Official title: Restrictive Fluid Administration vs. Standard of Care in Emergency Department Sepsis Patients - a Multicenter, Randomized Clinical Feasibility Trial (REFACED Sepsis)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Sepsis
Keywords: Sepsis
Hypotension
IV fluid therapy
Fluid resuscitation
Emergency Department
Crystalloids
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: University of Aarhus
name: Aarhus University Hospital
name: Viborg Regional Hospital
name: Randers Regional Hospital
First posted: 2021-10-13
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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

Eligibility criteria: Inclusion Criteria: All of the below must be fulfilled:

1. Unplanned emergency department admission
2. Age ≥ 18 years
3. Sepsis defined as

   1. suspected infection by the treating clinician AND
   2. blood cultures drawn AND
   3. IV antibiotics administered or planned AND
   4. An infection related increase of SOFA\*-score ≥ 2 from baseline
4. 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:

1. ≥ 500 ml of fluids given prior to randomization
2. Invasively ventilated or vasopressors initiated at the time of screening
3. Known or suspected severe bleeding judged by the treating clinician
4. Known or suspected pregnancy (women aged \<45 years will have a pregnancy test performed before enrollment)
5. Prior enrollment in the trial
6. Patients, who the clinician expect not to survive the next 24-hours

Primary outcomes:
measure: 24-hour crystalloid iv. fluids
timeFrame: 24 hours from randomization
Secondary outcomes:
measure: Protocol violations
timeFrame: 24 hours from randomization
measure: Screened-vs.-randomized-ratio
timeFrame: Through study completion, an average of 1 year
measure: Time to inclusion
timeFrame: Through study completion, an average of 1 year
measure: Lost-to-follow-up-rate
timeFrame: 24 hours from randomization
measure: Accumulated serious adverse reactions (SARs + SUSARs)
timeFrame: 7 days from randomization
measure: Total 24-hour fluids
timeFrame: 24 hours from randomization
measure: Mortality
timeFrame: Total of 90-days
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Department of Emergency Medicine, Aarhus University Hospital
state: Central Denmark Region
city: Randers
country: Denmark
facility: Department of Emergency Medicine, Regional Hospital Randers
state: Central Denmark Region
city: Viborg
country: Denmark
facility: Department of Emergency Medicine, Regional Hospital Viborg
state: Central Denmark Region
Study officials:
affiliation: Research Center for Emergency Medicine, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Denmark
name: Marie K Jessen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jessen MK, Andersen LW, Thomsen MH, Kristensen P, Hayeri W, Hassel RE, Perner A, Petersen JAK, Kirkegaard H. Restrictive Fluid Administration vs. Standard of Care in Emergency Department Sepsis Patients (REFACED Sepsis)-protocol for a multicenter, randomized, clinical, proof-of-concept trial. Pilot Feasibility Stud. 2022 Mar 29;8(1):75. doi: 10.1186/s40814-022-01034-y.