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

• ClinicalTrials.gov Identifier: NCT05076435
• Recruitment Status: Completed
• First Posted: October 13, 2021
• Last Update Posted: March 25, 2022
• Sponsor: Marie Kristine Jessen, MD
• Collaborators: University of Aarhus; Aarhus University Hospital; Viborg Regional Hospital; Randers Regional Hospital
• Information provided by (Responsible Party): Marie Kristine Jessen, MD, University of Aarhus

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Sepsis	Drug: Isotonic crystalloids	Phase 2

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 124 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Restrictive Fluid Administration vs. Standard of Care in Emergency Department Sepsis Patients - a Multicenter, Randomized Clinical Feasibility Trial (REFACED Sepsis)
• Actual Study Start Date: November 3, 2021
• Actual Primary Completion Date: December 19, 2021
• Actual Study Completion Date: March 19, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Restrictive fluid administration; 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; 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.
Active Comparator: Usual care (standard care); 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; 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.

Outcome Measures

Primary Outcome Measures :

1. 24-hour crystalloid iv. fluids [ Time Frame: 24 hours from randomization ]
   total amount of all administered intravenous, crystalloid fluids within 24 hours of randomization

Secondary Outcome Measures :

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

Eligibility Criteria

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

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

Contacts and Locations

Locations

Denmark

Department of Emergency Medicine, Aarhus University Hospital

Aarhus, Central Denmark Region, Denmark, 8200

Department of Emergency Medicine, Regional Hospital Randers

Randers, Central Denmark Region, Denmark, 8930

Department of Emergency Medicine, Regional Hospital Viborg

Viborg, Central Denmark Region, Denmark, 8800

Sponsors and Collaborators

Marie Kristine Jessen, MD

University of Aarhus

Aarhus University Hospital

Viborg Regional Hospital

Randers Regional Hospital

Investigators

• Principal Investigator: Marie K Jessen, MD; Research Center for Emergency Medicine, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Denmark

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Marie Kristine Jessen, MD, Principal Investigator, University of Aarhus
• ClinicalTrials.gov Identifier: NCT05076435
• Other Study ID Numbers: RECEM0001; 2021-000224-35 ( EudraCT Number ); 1-10-72-163-21 ( Other Identifier: The Committee on Health Research Ethics, Central Denmark Region )
• First Posted: October 13, 2021
• Last Update Posted: March 25, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Marie Kristine Jessen, MD, University of Aarhus:

Sepsis; Hypotension; IV fluid therapy; Fluid resuscitation; Emergency Department; Crystalloids

Additional relevant MeSH terms:

Sepsis; Toxemia; Emergencies; Disease Attributes; Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation