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

NCT03668236 | Completed Phase 4 Results DMC

• 1 other identifier: RH-ITA-007
• Study Type: interventional
• Target: 1,554
• Locations: 8 countries
• Sites: 31

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.

Conditions

Septic Shock

Keywords

Fluid resuscitation; Critical care; Intensive care; Crystalloid; IV fluid therapy

Outcome Measures

Primary Outcomes (1)

• 90-day Mortality

  Al cause mortality at 90 days

  Day 90 after randomisation

Secondary Outcomes (7)

• Number of Participants With One or More Serious Adverse Events (SAEs) in the ICU

  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

Study Arms (2)

Fluid restriction group

EXPERIMENTAL

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

Drug: Isotonic crystalloids

Standard-care

ACTIVE COMPARATOR

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

Drug: Isotonic crystalloids

Interventions

Isotonic crystalloids 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

Fluid restriction group; Standard-care

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Anders Perner, MD, PhD: lead
• Rigshospitalet, Denmark: collaborator
• Centre for Research in Intensive Care (CRIC): collaborator
• Scandinavian Critical Care Trials Group: collaborator

Study Sites (31)

University Hospital Brussels (UZB)

Brussels, Belgium

Location

Medical Intensive Care Unit, Fakultni Nemocnice

Pilsen, Czechia

Location

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

Aalborg, Denmark

Location

Dept of Intensive Care,Copenhagen University Hospital Rigshospitalet

Copenhagen, 2100, Denmark

Location

Dept. of Anaesthesia and Intensive Care, Bispebjerg Hospital

Copenhagen, Denmark

Location

Dept. of Anaesthesia and Intensive Care, Herning Hospital

Herning, Denmark

Location

Dept. of Intensive Care, Hillerød Hospital

Hillerød, 3400, Denmark

Location

Dept. of Anaesthesia and Intensive Care, Holbæk Hospital

Holbæk, Denmark

Location

Dept. of Anaesthesia and Intensive Care, Lillebaelt Hospital

Kolding, Denmark

Location

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

Køge, Denmark

Location

Dept. of Anaesthesia and Intensive Care, Randers Hospital

Randers, Denmark

Location

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

Roskilde, Denmark

Location

Dept. of Anaesthesia and Intensive Care, Viborg Hospital

Viborg, Denmark

Location

Humanitas research hospital Bergamo

Bergamo, Milan, Italy

Location

Dept. of Intensive Care, Humanitas Research Hospital Castelanza

Castellanza, Milan, Italy

Location

Dept. of Intensive Care, Ancona Hospital

Ancona, Italy

Location

Dept. of Intensive Care, Humanitas Research Hospital

Milan, Italy

Location

Dept. of intensive care, Østfold, Kalnes

Grålum, Norway

Location

Dept. of intensive Care, Innlandet Hamar

Hamar, Norway

Location

Dept. of Intensive Care, Oslo University Hospital

Oslo, 0450, Norway

Location

Dept. of Intensive Care Medicine, Stavanger

Stavanger, Norway

Location

Dept. of Intensive Care Medicine, St Göran

Gothenburg, Sweden

Location

Dept. of intensive care, Huddinge

Huddinge, Sweden

Location

MIMA Medicinsk intermediärvårdsavdelning

Huddinge, Sweden

Location

Dept. of Intensive Care, Solna

Solna, Sweden

Location

Medical ICU, Karolinska, Södersjukhuset

Stockholm, Sweden

Location

Södersjukhuset

Stockholm, Sweden

Location

Dept. of Intensive Care Medicine Sundsvall Hospital

Sundsvall, Sweden

Location

Dept. of intensive care, Basel

Basel, Switzerland

Location

Dept. of Intensive Care, University Hospital Bern

Bern, Switzerland

Location

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

London, United Kingdom

Location

Related Publications (8)

• 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.

  PMID: 27686349 BACKGROUND

• 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.

  PMID: 35709019 BACKGROUND

• 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.

  PMID: 31276193 BACKGROUND

• 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.

  PMID: 40272936 DERIVED

• 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.

  PMID: 38576165 DERIVED

• 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.

  PMID: 37330928 DERIVED

• 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.

  PMID: 31982391 DERIVED

• 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.

  PMID: 31828753 DERIVED

Related Links

• Official study website

MeSH Terms

Conditions

Shock, Septic

Condition Hierarchy (Ancestors)

Sepsis; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Results Point of Contact

• Title: Prof. Anders Perner
• Organization: Rigshospitalet, University of Copenhagen

anders.perner@regionh.dk

+45 35458333

Study Officials

• Tine Sylvest Meyhoff, MD

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Outcome assessor- and analyst-blinded trial
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, PhD, Senior staff specialist , Professor in Intensive Care

Study Record Dates

• First Submitted: September 6, 2018
• First Posted: September 12, 2018
• Study Start: November 27, 2018
• Primary Completion: February 14, 2022
• Study Completion: November 16, 2022
• Last Updated: February 24, 2025
• Results First Posted: February 24, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share

Locations

BE (1); CZ (1); NO (4); GB (1); DK (11); SE (7); CH (2); IT (4)