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

Rigshospitalet, Denmark, Centre for Research in Intensive Care (CRIC), Scandinavian Critical Care Trials Group

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.

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%.

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

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

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

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)

Number of participants with one or more serious adverse reactions (SARs) to IV crystalloids in the ICU.

Days alive at day 90 without life support (vasopressor / inotropic support, invasive mechanical ventilation or renal replacement therapy)

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.

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.

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

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, 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, 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.