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

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.

Study Overview

• Status: Completed
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Isotonic crystalloids

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%.

• Study Type: Interventional
• Enrollment (Actual): 1554
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium
    • University Hospital Brussels (UZB)
• Czechia
  • Plzen, Czechia
    • Medical Intensive Care Unit, Fakultni Nemocnice
• Denmark
  • Aalborg, Denmark
    • Dept. of Anaesthesia and Intensive Care, Aalborg University Hospital, Denmark.
  • Copenhagen, Denmark
    • Dept. of Anaesthesia and Intensive Care, Bispebjerg Hospital
  • Copenhagen, Denmark, 2100
    • Dept of Intensive Care,Copenhagen University Hospital Rigshospitalet
  • Herning, Denmark
    • Dept. of Anaesthesia and Intensive Care, Herning Hospital
  • Hillerød, Denmark, 3400
    • Dept. of Intensive Care, Hillerød Hospital
  • Holbæk, Denmark
    • Dept. of Anaesthesia and Intensive Care, Holbæk Hospital
  • Kolding, Denmark
    • Dept. of Anaesthesia and Intensive Care, Lillebaelt Hospital
  • Køge, Denmark
    • Dept. of Anaesthesia and Intensive Care, Zealand University Hospital Køge
  • Randers, Denmark
    • Dept. of Anaesthesia and Intensive Care, Randers Hospital
  • Roskilde, Denmark
    • Dept. of Anaesthesia and Intensive Care, Zealand University Hospital Roskilde
  • Viborg, Denmark
    • Dept. of Anaesthesia and Intensive Care, Viborg Hospital
• Italy
  • Ancona, Italy
    • Dept. of Intensive Care, Ancona Hospital
  • Milan, Italy
    • Dept. of Intensive Care, Humanitas Research Hospital
  • Milan
    • Bergamo, Milan, Italy
      • Humanitas research hospital Bergamo
    • Castellanza, Milan, Italy
      • Dept. of Intensive Care, Humanitas Research Hospital Castelanza
• Norway
  • Grålum, Norway
    • Dept. of intensive care, Østfold, Kalnes
  • Hamar, Norway
    • Dept. of intensive Care, Innlandet Hamar
  • Oslo, Norway, 0450
    • Dept. of Intensive Care, Oslo University Hospital
  • Stavanger, Norway
    • Dept. of Intensive Care Medicine, Stavanger
• Sweden
  • Gothenburg, Sweden
    • Dept. of Intensive Care Medicine, St Göran
  • Huddinge, Sweden
    • Dept. of intensive care, Huddinge
  • Huddinge, Sweden
    • MIMA Medicinsk intermediärvårdsavdelning
  • Solna, Sweden
    • Dept. of Intensive Care, Solna
  • Stockholm, Sweden
    • Sodersjukhuset
  • Stockholm, Sweden
    • Medical ICU, Karolinska, Södersjukhuset
  • Sundsvall, Sweden
    • Dept. of Intensive Care Medicine Sundsvall Hospital
• Switzerland
  • Basel, Switzerland
    • Dept. of intensive care, Basel
  • Bern, Switzerland
    • Dept. of Intensive Care, University Hospital Bern
• United Kingdom
  • London, United Kingdom
    • Dept. of Intensive Care Unit, Guy's and St. Thomas' Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fluid restriction group; 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/LMAP<50 mmHg (with or without vasopressor/inotrope)Mottling beyond the kneecap (mottling score >2) ORUrinary output<0.1 mL/kg bodyweight/h, but only in the first 2hrs after randomisationA 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 deficienciesEnsure 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; 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
Active Comparator: Standard-care; 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; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
90-day Mortality	Al cause mortality at 90 days	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	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)	Until ICU discharge, maximum 90 days
Number of Participants With One or More Serious Adverse Reactions (SARs) to IV Crystalloids in the ICU.	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.	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	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	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.	1-year after randomisation

Collaborators and Investigators

• Sponsor: Anders Perner, MD, PhD
• Collaborators: Rigshospitalet, Denmark; Scandinavian Critical Care Trials Group; Centre for Research in Intensive Care (CRIC)
• Investigators: Principal Investigator: Tine Sylvest Meyhoff, MD, Rigshospitalet, Denmark

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• Official study website

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2018
• Primary Completion (Actual): February 14, 2022
• Study Completion (Actual): November 16, 2022

Study Registration Dates

• First Submitted: September 6, 2018
• First Submitted That Met QC Criteria: September 10, 2018
• First Posted (Actual): September 12, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 21, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Critical care; Fluid resuscitation; Crystalloid; Intensive care; IV fluid therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Shock, Septic
• Other Study ID Numbers: RH-ITA-007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No