The Conservative vs. Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care Trial

Phase 4

Completed

Conditions: Septic Shock

Interventions: Drug: Isotonic crystalloids

Registration Number: NCT03668236

Lead Sponsor: Anders Perner, MD, PhD

Brief Summary: The purpose of this trial is to assess patient important benefits and harms of IV fluid restriction vs. standard care fluid therapy in patients with septic shock.

Detailed Description: BACKGROUND:

Septic shock is common, often lethal, costly, and associated with prolonged suffering among survivors and relatives. Traditionally, intravenous (IV) fluids are used to optimise the circulation, and the use of higher volumes is recommended by international guidelines. There is, however, no high-quality evidence to support this. In contrast, data from cohort studies, small trials and systematic reviews in sepsis and large trials in other settings and patient groups suggest potential benefits from restriction of IV fluids in patients with septic shock.

OBJECTIVES:

The aim of the CLASSIC trial is to assess the benefits and harms of IV fluid restriction vs. standard care on patient-important outcome measures in adult intensive care unit (ICU) patients with septic shock.

DESIGN:

CLASSIC is an international, multicentre, parallel-grouped, open-labelled, centrally randomised, stratified, outcome assessor- and analyst-blinded trial.

POPULATION:

Adult ICU patients who have septic shock and have received at least 1 L of IV fluid in the last 24-hours.

EXPERIMENTAL INTERVENTION:

In the IV fluid restriction group no IV fluids should be given in the ICU unless extenuating circumstances occur, including signs of severe hypoperfusion, overt fluid loss or a failing GI tract with a total fluid input of less than 1 L per day. In these circumstances, IV fluid may be given in measured amounts.

CONTROL INTERVENTION:

In the standard care group there will be no upper limit for the use of IV fluids.

OUTCOMES:

The primary outcome is 90-day mortality; secondary outcomes are serious adverse events in the ICU (ischemic events or severe acute kidney injury); serious adverse reactions in the ICU; days alive without life support at day 90; days alive and out of hospital at day 90 and mortality, health-related quality of life and cognitive function at 1-year.

TRIAL SIZE:

A total of 1554 participants will be randomised to allow the detection of a 15% relative risk reduction (7% absolute) in the restrictive vs. standard care group in 90-day mortality with a power of 80%.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1554

Inclusion Criteria

All the following criteria must be fulfilled:

Aged 18 years or above
Admitted to the ICU or plan to be admitted to the ICU regardless of trial participation
Septic shock defined according to the Sepsis-3 criteria:
- Suspected or confirmed site of infection or positive blood culture AND
- Ongoing infusion of vasopressor/inotrope agent to maintain a mean arterial blood pressure of 65 mmHg or above AND
- Lactate of 2 mmol/L or above in any plasma sample performed within the last 3-hours
Have received at least 1 L of IV fluid (crystalloids, colloids or blood products) in the last 24-hours prior to screening.

Exclusion Criteria

Patients who fulfil any of the following criteria will be excluded:

Septic shock for more than 12 hours at the time of screening as these patients are no longer early in their course
Life-threatening bleeding as these patients need specific fluid/blood product strategies
Acute burn injury of more than 10% of the body surface area as these patients need a specific fluid strategy
Known pregnancy
Consent not obtainable as per the model approved for the specific site

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fluid restriction group	Isotonic crystalloids	No IV fluids unless one of the extenuating circumstances occur; then, IV fluid may be given in measured amounts: 1. In case of severe hypoperfusion or severe circulatory impairment defined by either: * Lactate≥4 mmol/L * MAP\<50 mmHg (with or without vasopressor/inotrope) * Mottling beyond the kneecap (mottling score \>2) OR * Urinary output\<0.1 mL/kg bodyweight/h, but only in the first 2hrs after randomisation A bolus of 250-500 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 1L per 24hrs IV fluids may be given as carrier for medication, but the volume should be reduced to the lowest possible
Standard-care	Isotonic crystalloids	There will be no upper limit for the use of either IV or oral/enteral fluids. In particular: 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
90-day Mortality	Day 90 after randomisation	Al cause mortality at 90 days

Secondary Outcome Measures

Name	Time	Method
Number of Participants With One or More Serious Adverse Events (SAEs) in the ICU	Until ICU discharge, maximum 90 days	SAEs were defined as ischaemic events (cerebral, cardiac, intestinal or limb ischaemia) or as a new episode of severe acute kidney injury (modified KDIGO-3)
Number of Participants With One or More Serious Adverse Reactions (SARs) to IV Crystalloids in the ICU.	Until ICU discharge, maximum 90 days	The pre-specified SARs to IV crystalloids were: Generalized tonic-clonic seizures, anaphylactic reactions, central pontine myelinolysis, severe hypernatremia, severe hyperchloremic acidosis, and severe metabolic alkalosis. Data on the outcome measures, including SARs, were obtained from patient medical records by the trial investigators or their delegates.
Days Alive at Day 90 Without Life Support (Vasopressor / Inotropic Support, Invasive Mechanical Ventilation or Renal Replacement Therapy)	Until ICU discharge, maximum 90 days
Days Alive and Out of Hospital at Day 90	Day 90 after randomisation
All-cause Mortality at 1-year After Randomisation	1-year after randomisation
Health-related Quality of Life 1 Year After Randomisation	1 year after randomisation	Measured using the EuroQoL EQ-5D-5L questionnaire (comprising 5 questions with a score from 1 to 5 each and a visual analogue scale from 0 to 100). Participants who have died will be assigned the lowest possible scores.
Cognitive Function 1-year After Randomisation	1-year after randomisation	Assessed by the Montreal Cognitive Assessment (MoCa) MINI score validated for telephone use. Mini MoCA consists of 4 cognitive dimensions: attention (immediate recall of 5 words), executive functions and language (1-min verbal fluency), orientation (6 items on date and geographic orientation), and memory (delayed recall and recognition of 5 previously learned words). The total score ranges from 0 to 30, with lower values indicating worse cognitive function. To correct for any educational effect on the cognitive test, 1 point is added for participants with 12 years of education or less (scores were truncated at the maximum upper value of 30 points) Participants who had died were assigned the value 0.

Trial Locations

Locations (31): Dept. of Intensive Care Medicine, Stavanger
🇳🇴
Stavanger, Norway
Dept. of intensive care, Basel
🇨🇭
Basel, Switzerland
Dept. of Intensive Care, University Hospital Bern
🇨🇭
Bern, Switzerland
Dept. of Intensive Care, Ancona Hospital
🇮🇹
Ancona, Italy
Dept. of Anaesthesia and Intensive Care, Holbæk Hospital
🇩🇰
Holbæk, Denmark
Dept. of Intensive Care, Humanitas Research Hospital
🇮🇹
Milan, Italy
Dept. of intensive care, Huddinge
🇸🇪
Huddinge, Sweden
Dept. of intensive Care, Innlandet Hamar
🇳🇴
Hamar, Norway
Dept. of Anaesthesia and Intensive Care, Bispebjerg Hospital
🇩🇰
Copenhagen, Denmark
Dept. of Intensive Care, Oslo University Hospital
🇳🇴
Oslo, Norway
Dept. of Intensive Care Medicine, St Göran
🇸🇪
Gothenburg, Sweden
Humanitas research hospital Bergamo
🇮🇹
Bergamo, Milan, Italy
Södersjukhuset
🇸🇪
Stockholm, Sweden
Dept. of Intensive Care Unit, Guy's and St. Thomas' Hospital
🇬🇧
London, United Kingdom
Dept of Intensive Care,Copenhagen University Hospital Rigshospitalet
🇩🇰
Copenhagen, Denmark
Dept. of Intensive Care, Hillerød Hospital
🇩🇰
Hillerød, Denmark
Dept. of Anaesthesia and Intensive Care, Lillebaelt Hospital
🇩🇰
Kolding, Denmark
Dept. of Anaesthesia and Intensive Care, Randers Hospital
🇩🇰
Randers, Denmark
Dept. of Anaesthesia and Intensive Care, Zealand University Hospital Roskilde
🇩🇰
Roskilde, Denmark
Dept. of Anaesthesia and Intensive Care, Viborg Hospital
🇩🇰
Viborg, Denmark
MIMA Medicinsk intermediärvårdsavdelning
🇸🇪
Huddinge, Sweden
Dept. of Intensive Care, Solna
🇸🇪
Solna, Sweden
University Hospital Brussels (UZB)
🇧🇪
Brussel, Belgium
Dept. of Anaesthesia and Intensive Care, Aalborg University Hospital, Denmark.
🇩🇰
Aalborg, Denmark
Medical Intensive Care Unit, Fakultni Nemocnice
🇨🇿
Plzen, Czechia
Dept. of Anaesthesia and Intensive Care, Herning Hospital
🇩🇰
Herning, Denmark
Dept. of Anaesthesia and Intensive Care, Zealand University Hospital Køge
🇩🇰
Køge, Denmark
Dept. of Intensive Care, Humanitas Research Hospital Castelanza
🇮🇹
Castellanza, Milan, Italy
Dept. of intensive care, Østfold, Kalnes
🇳🇴
Grålum, Norway
Medical ICU, Karolinska, Södersjukhuset
🇸🇪
Stockholm, Sweden
Dept. of Intensive Care Medicine Sundsvall Hospital
🇸🇪
Sundsvall, Sweden