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

Study Overview
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Brief Summary
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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
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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%.

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

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: Isotonic crystalloids


Participation Criteria
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Eligibility Criteria
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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

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fluid restriction group<br>No IV fluids unless one of the extenuating circumstances occur; then, IV fluid may be given in measured amounts: 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 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 1L per 24hrs IV fluids may be given as carrier for medication, but the volume should be reduced to the lowest possible | Drug: Isotonic crystalloids<br>* Types of fluid to be used in both intervention groups: IV fluids given for circulatory impairment: Only isotonic crystalloids are to be used as per the Scandinavian guideline for fluid resuscitation 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 Fluids used for dehydration: Water or isotonic glucose should be used Fluids used for electrolyte disturbances: Fluids should be chosen to substitute the specific deficiency, including water in the case of severe hypernatremia 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: Standard-care<br>There will be no upper limit for the use of either IV or oral/enteral fluids. In particular: 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 fluid to be used in both intervention groups: IV fluids given for circulatory impairment: Only isotonic crystalloids are to be used as per the Scandinavian guideline for fluid resuscitation 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 Fluids used for dehydration: Water or isotonic glucose should be used Fluids used for electrolyte disturbances: Fluids should be chosen to substitute the specific deficiency, including water in the case of severe hypernatremia 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 |
| --- | --- | --- |
| 90-day mortality |  | Day 90 after randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with one or more serious adverse events (SAEs) in the ICU defined as ischaemic events (cerebral, cardiac, intestinal or limb ischaemia) or as a new episode of severe acute kidney injury (modified KDIGO-3) |  | Until ICU discharge, maximum 90 days | 
| Number of participants with one or more serious adverse reactions (SARs) to IV crystalloids in the ICU. |  | Until ICU discharge, maximum 90 days | 
| 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 | Will be 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. | 1-year after randomisation | 
| Cognitive function 1-year after randomisation | Will be assessed by the Montreal Cognitive Assessment (MoCa) MINI score which is soon to be released. Participants who have died will be assigned the lowest possible score. | 1-year after randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fluid resuscitation, Critical care, Intensive care, Crystalloid, IV fluid therapy