Clinical trial NCT03668236: The Conservative vs. Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care Trial
Official title: The Conservative vs. Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Septic Shock
Keywords: Fluid resuscitation
Critical care
Intensive care
Crystalloid
IV fluid therapy
Lead sponsor: Scandinavian Critical Care Trials Group
Sponsor class: OTHER
Collaborators: name: Rigshospitalet, Denmark
name: Centre for Research in Intensive Care (CRIC)
name: Scandinavian Critical Care Trials Group
First posted: 2018-09-12
Enrollment: 1554
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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%.

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

Primary outcomes:
measure: 90-day Mortality
timeFrame: Day 90 after randomisation
Secondary outcomes:
measure: Number of Participants With One or More Serious Adverse Events (SAEs) in the ICU
timeFrame: Until ICU discharge, maximum 90 days
measure: Number of Participants With One or More Serious Adverse Reactions (SARs) to IV Crystalloids in the ICU.
timeFrame: Until ICU discharge, maximum 90 days
measure: Days Alive at Day 90 Without Life Support (Vasopressor / Inotropic Support, Invasive Mechanical Ventilation or Renal Replacement Therapy)
timeFrame: Until ICU discharge, maximum 90 days
measure: Days Alive and Out of Hospital at Day 90
timeFrame: Day 90 after randomisation
measure: All-cause Mortality at 1-year After Randomisation
timeFrame: 1-year after randomisation
measure: Health-related Quality of Life 1 Year After Randomisation
timeFrame: 1 year after randomisation
measure: Cognitive Function 1-year After Randomisation
timeFrame: 1-year after randomisation
Other outcomes:
Locations:
city: Brussel
country: Belgium
facility: University Hospital Brussels (UZB)
city: Plzen
country: Czechia
facility: Medical Intensive Care Unit, Fakultni Nemocnice
city: Aalborg
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Aalborg University Hospital, Denmark.
city: Copenhagen
country: Denmark
facility: Dept of Intensive Care,Copenhagen University Hospital Rigshospitalet
city: Copenhagen
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Bispebjerg Hospital
city: Herning
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Herning Hospital
city: Hillerød
country: Denmark
facility: Dept. of Intensive Care, Hillerød Hospital
city: Holbæk
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Holbæk Hospital
city: Kolding
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Lillebaelt Hospital
city: Køge
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Zealand University Hospital Køge
city: Randers
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Randers Hospital
city: Roskilde
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Zealand University Hospital Roskilde
city: Viborg
country: Denmark
facility: Dept. of Anaesthesia and Intensive Care, Viborg Hospital
city: Bergamo
country: Italy
facility: Humanitas research hospital Bergamo
state: Milan
city: Castellanza
country: Italy
facility: Dept. of Intensive Care, Humanitas Research Hospital Castelanza
state: Milan
city: Ancona
country: Italy
facility: Dept. of Intensive Care, Ancona Hospital
city: Milan
country: Italy
facility: Dept. of Intensive Care, Humanitas Research Hospital
city: Grålum
country: Norway
facility: Dept. of intensive care, Østfold, Kalnes
city: Hamar
country: Norway
facility: Dept. of intensive Care, Innlandet Hamar
city: Oslo
country: Norway
facility: Dept. of Intensive Care, Oslo University Hospital
city: Stavanger
country: Norway
facility: Dept. of Intensive Care Medicine, Stavanger
city: Gothenburg
country: Sweden
facility: Dept. of Intensive Care Medicine, St Göran
city: Huddinge
country: Sweden
facility: Dept. of intensive care, Huddinge
city: Huddinge
country: Sweden
facility: MIMA Medicinsk intermediärvårdsavdelning
city: Solna
country: Sweden
facility: Dept. of Intensive Care, Solna
city: Stockholm
country: Sweden
facility: Medical ICU, Karolinska, Södersjukhuset
city: Stockholm
country: Sweden
facility: Södersjukhuset
city: Sundsvall
country: Sweden
facility: Dept. of Intensive Care Medicine Sundsvall Hospital
city: Basel
country: Switzerland
facility: Dept. of intensive care, Basel
city: Bern
country: Switzerland
facility: Dept. of Intensive Care, University Hospital Bern
city: London
country: United Kingdom
facility: Dept. of Intensive Care Unit, Guy's and St. Thomas' Hospital
Study officials:
affiliation: Rigshospitalet, Denmark
name: Tine Sylvest Meyhoff, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.