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

NCT ID: NCT03668236

Last Updated: 2025-02-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 1554 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-11-27
• Study Completion Date: 2022-11-16

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%.

Conditions

Septic Shock

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Fluid restriction group

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

Group Type: EXPERIMENTAL

Isotonic crystalloids

Intervention Type: DRUG

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

Standard-care

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

Group Type: ACTIVE_COMPARATOR

Isotonic crystalloids

Intervention Type: DRUG

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

Interventions

Isotonic crystalloids

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

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Rigshospitalet, Denmark

OTHER

Sponsor Role: collaborator

Centre for Research in Intensive Care (CRIC)

OTHER

Sponsor Role: collaborator

Scandinavian Critical Care Trials Group

OTHER

Sponsor Role: collaborator

Anders Perner, MD, PhD

OTHER

Sponsor Role: lead

Responsible Party

Anders Perner, MD, PhD

MD, PhD, Senior staff specialist , Professor in Intensive Care

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Tine Sylvest Meyhoff, MD

Role: PRINCIPAL_INVESTIGATOR

Rigshospitalet, Denmark

Locations

University Hospital Brussels (UZB)

Brussels, , Belgium

Medical Intensive Care Unit, Fakultni Nemocnice

Pilsen, , Czechia

Dept. of Anaesthesia and Intensive Care, Aalborg University Hospital, Denmark.

Aalborg, , Denmark

Dept of Intensive Care,Copenhagen University Hospital Rigshospitalet

Copenhagen, , Denmark

Dept. of Anaesthesia and Intensive Care, Bispebjerg Hospital

Copenhagen, , Denmark

Dept. of Anaesthesia and Intensive Care, Herning Hospital

Herning, , Denmark

Dept. of Intensive Care, Hillerød Hospital

Hillerød, , Denmark

Dept. of Anaesthesia and Intensive Care, Holbæk Hospital

Holbæk, , Denmark

Dept. of Anaesthesia and Intensive Care, Lillebaelt Hospital

Kolding, , Denmark

Dept. of Anaesthesia and Intensive Care, Zealand University Hospital Køge

Køge, , 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

Humanitas research hospital Bergamo

Bergamo, Milan, Italy

Dept. of Intensive Care, Humanitas Research Hospital Castelanza

Castellanza, Milan, Italy

Dept. of Intensive Care, Ancona Hospital

Ancona, , Italy

Dept. of Intensive Care, Humanitas Research Hospital

Milan, , Italy

Dept. of intensive care, Østfold, Kalnes

Grålum, , Norway

Dept. of intensive Care, Innlandet Hamar

Hamar, , Norway

Dept. of Intensive Care, Oslo University Hospital

Oslo, , Norway

Dept. of Intensive Care Medicine, Stavanger

Stavanger, , Norway

Dept. of Intensive Care Medicine, St Göran

Gothenburg, , Sweden

Dept. of intensive care, Huddinge

Huddinge, , Sweden

MIMA Medicinsk intermediärvårdsavdelning

Huddinge, , Sweden

Dept. of Intensive Care, Solna

Solna, , Sweden

Medical ICU, Karolinska, Södersjukhuset

Stockholm, , Sweden

Södersjukhuset

Stockholm, , Sweden

Dept. of Intensive Care Medicine Sundsvall Hospital

Sundsvall, , Sweden

Dept. of intensive care, Basel

Basel, , Switzerland

Dept. of Intensive Care, University Hospital Bern

Bern, , Switzerland

Dept. of Intensive Care Unit, Guy's and St. Thomas' Hospital

London, , United Kingdom

Countries

Belgium; Czechia; Denmark; Italy; Norway; Sweden; Switzerland; United Kingdom

References

Hjortrup PB, Haase N, Bundgaard H, Thomsen SL, Winding R, Pettila V, Aaen A, Lodahl D, Berthelsen RE, Christensen H, Madsen MB, Winkel P, Wetterslev J, Perner A; CLASSIC Trial Group; Scandinavian Critical Care Trials Group. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med. 2016 Nov;42(11):1695-1705. doi: 10.1007/s00134-016-4500-7. Epub 2016 Sep 30.

Reference Type: BACKGROUND

PMID: 27686349 (View on PubMed)

Meyhoff TS, Hjortrup PB, Wetterslev J, Sivapalan P, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain M, Pettila V, Moller MH, Kjaer MN, Lange T, Overgaard-Steensen C, Brand BA, Winther-Olesen M, White JO, Quist L, Westergaard B, Jonsson AB, Hjortso CJS, Meier N, Jensen TS, Engstrom J, Nebrich L, Andersen-Ranberg NC, Jensen JV, Joseph NA, Poulsen LM, Herlov LS, Solling CG, Pedersen SK, Knudsen KK, Straarup TS, Vang ML, Bundgaard H, Rasmussen BS, Aagaard SR, Hildebrandt T, Russell L, Bestle MH, Schonemann-Lund M, Brochner AC, Elvander CF, Hoffmann SKL, Rasmussen ML, Martin YK, Friberg FF, Seter H, Aslam TN, Adnoy S, Seidel P, Strand K, Johnstad B, Joelsson-Alm E, Christensen J, Ahlstedt C, Pfortmueller CA, Siegemund M, Greco M, Radej J, Kriz M, Gould DW, Rowan KM, Mouncey PR, Perner A; CLASSIC Trial Group. Restriction of Intravenous Fluid in ICU Patients with Septic Shock. N Engl J Med. 2022 Jun 30;386(26):2459-2470. doi: 10.1056/NEJMoa2202707. Epub 2022 Jun 17.

Reference Type: BACKGROUND

PMID: 35709019 (View on PubMed)

Meyhoff TS, Hjortrup PB, Moller MH, Wetterslev J, Lange T, Kjaer MN, Jonsson AB, Hjortso CJS, Cronhjort M, Laake JH, Jakob SM, Nalos M, Pettila V, van der Horst I, Ostermann M, Mouncey P, Rowan K, Cecconi M, Ferrer R, Malbrain MLNG, Ahlstedt C, Hoffmann S, Bestle MH, Nebrich L, Russell L, Vang M, Rasmussen ML, Solling C, Rasmussen BS, Brochner AC, Perner A. Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial-Protocol and statistical analysis plan. Acta Anaesthesiol Scand. 2019 Oct;63(9):1262-1271. doi: 10.1111/aas.13434. Epub 2019 Jul 24.

Reference Type: BACKGROUND

PMID: 31276193 (View on PubMed)

Sivapalan P, Kaas-Hansen BS, Meyhoff TS, Hjortrup PB, Kjaer MN, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain MLNG, Moller MH, Perner A, Granholm A. Effects of IV Fluid Restriction According to Standard Fluid Treatment Intensity Across Conservative Versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) Trial Sites. Crit Care Med. 2025 Aug 1;53(8):e1590-e1600. doi: 10.1097/CCM.0000000000006679. Epub 2025 Apr 24.

Reference Type: DERIVED

PMID: 40272936 (View on PubMed)

Sivapalan P, Kaas-Hansen BS, Meyhoff TS, Hjortrup PB, Kjaer MN, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain MLNG, Moller MH, Perner A, Granholm A. Effects of IV fluid restriction according to site-specific intensity of standard fluid treatment-protocol. Acta Anaesthesiol Scand. 2024 Aug;68(7):975-982. doi: 10.1111/aas.14423. Epub 2024 Apr 4.

Reference Type: DERIVED

PMID: 38576165 (View on PubMed)

Kjaer MN, Meyhoff TS, Sivapalan P, Granholm A, Hjortrup PB, Madsen MB, Moller MH, Egerod I, Wetterslev J, Lange T, Cronhjort M, Laake JH, Jakob SM, Nalos M, Ostermann M, Gould D, Cecconi M, Malbrain MLNG, Ahlstedt C, Kiel LB, Bestle MH, Nebrich L, Hildebrandt T, Russell L, Vang M, Rasmussen ML, Solling C, Brochner AC, Krag M, Pfortmueller C, Kriz M, Siegemund M, Albano G, Aagaard SR, Bundgaard H, Crone V, Wichmann S, Johnstad B, Martin YK, Seidel P, Martensson J, Hollenberg J, Wistrand M, Donati A, Barbara E, Karvunidis T, Hollinger A, Carsetti A, Lumlertgul N, Joelsson-Alm E, Lambiris N, Aslam TN, Friberg FF, Vesterlund GK, Mortensen CB, Vestergaard SR, Caspersen SF, Jensen DB, Borup M, Rasmussen BS, Perner A. Long-term effects of restriction of intravenous fluid in adult ICU patients with septic shock. Intensive Care Med. 2023 Jul;49(7):820-830. doi: 10.1007/s00134-023-07114-8. Epub 2023 Jun 18.

Reference Type: DERIVED

PMID: 37330928 (View on PubMed)

Meyhoff TS, Moller MH, Hjortrup PB, Cronhjort M, Perner A, Wetterslev J. Lower vs Higher Fluid Volumes During Initial Management of Sepsis: A Systematic Review With Meta-Analysis and Trial Sequential Analysis. Chest. 2020 Jun;157(6):1478-1496. doi: 10.1016/j.chest.2019.11.050. Epub 2020 Jan 23.

Reference Type: DERIVED

PMID: 31982391 (View on PubMed)

Kjaer MN, Meyhoff TS, Madsen MB, Hjortrup PB, Moller MH, Egerod I, Wetterslev J, Lange T, Cronhjort M, Laake JH, Jakob SM, Nalos M, Pettila V, van der Horst ICC, Ostermann M, Mouncey P, Cecconi M, Ferrer R, Malbrain MLNG, Ahlstedt C, Hoffmann S, Bestle MH, Gyldensted L, Nebrich L, Russell L, Vang M, Solling C, Brochner AC, Rasmussen BS, Perner A. Long-term patient-important outcomes after septic shock: A protocol for 1-year follow-up of the CLASSIC trial. Acta Anaesthesiol Scand. 2020 Mar;64(3):410-416. doi: 10.1111/aas.13519. Epub 2019 Dec 26.

Reference Type: DERIVED

PMID: 31828753 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://www.cric.nu/classic/

Official study website

Other Identifiers

RH-ITA-007

Identifier Type: -

Identifier Source: org_study_id