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

Phase 2

Completed

• Conditions: Sepsis
• Interventions: Drug: Isotonic crystalloids

• Registration Number: NCT05076435
• Lead Sponsor: Marie Kristine Jessen, MD

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

Study Timeline

• Study First Submitted: 2021-09-11
• Study First Submitted QC: 2021-09-30
• Study First Posted: 2021-10-13
• Study Start: 2021-11-03
• Primary Completion: 2021-12-19
• Status Verified: 2022-03
• Study Completion: 2022-03-19
• Last Update Submitted: 2022-03-24
• Last Update Posted: 2022-03-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 124

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Restrictive fluid administration	Isotonic crystalloids	No IV fluids unless one of the extenuating circumstances occur; 1. 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 2. 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. 3. 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 4. IV fluids may be given as carrier for medication, but with lowest possible volume
Usual care (standard care)	Isotonic crystalloids	There will be no upper limit for the use of either IV or oral/enteral fluids 1. 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. 2. IV fluids should be given as maintenance if the ICU has a protocol recommending maintenance fluid 3. IV fluids should be given to substitute expected or observed loss, dehydration or electrolyte derangements

Primary Outcome Measures

Name	Time	Method
24-hour crystalloid iv. fluids	24 hours from randomization	total amount of all administered intravenous, crystalloid fluids within 24 hours of randomization

Secondary Outcome Measures

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

Trial Locations

Locations (3)

Department of Emergency Medicine, Aarhus University Hospital; 🇩🇰 Aarhus, Central Denmark Region, Denmark

Department of Emergency Medicine, Regional Hospital Randers; 🇩🇰 Randers, Central Denmark Region, Denmark

Department of Emergency Medicine, Regional Hospital Viborg; 🇩🇰 Viborg, Central Denmark Region, Denmark