BACKGROUNDIntravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU). METHODSIn this international, randomized trial, we assigned patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid to receive restricted intravenous fluid or standard intravenous fluid therapy; patients were included if the onset of shock had been within 12 hours before screening. The primary outcome was death from any cause within 90 days after randomization. RESULTSWe enrolled 1554 patients; 770 were assigned to the restrictive-fluid group and 784 to the standard-fluid group. Primary outcome data were available for 1545 patients (99.4%). In the ICU, the restrictive-fluid group received a median of 1798 ml of intravenous fluid (interquartile range, 500 to 4366); the standard-fluid group received a median of 3811 ml (interquartile range, 1861 to 6762). At 90 days, death had occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% confidence interval [CI], −4.7 to 4.9; P = 0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, −1.7 percentage points; 99% CI, −7.7 to 4.3). At 90 days after randomization, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups. CONCLUSIONSAmong adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy. (Funded by the Novo Nordisk Foundation and others; CLASSIC ClinicalTrials.gov number, NCT03668236.

Introduction Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the Conservative versus Liberal Approach to fluid therapy of Septic Shock in the Intensive Care (CLASSIC) trial. The aim of the CLASSIC trial is to assess benefits and harms of IV fluid restriction versus standard care in adult intensive care unit (ICU) patients with septic shock. Methods CLASSIC trial is an investigator-initiated, international, randomised, stratified, and analystblinded trial. We will allocate 1554 adult patients with septic shock, who are planned to be or are admitted to an ICU, to IV fluid restriction versus standard care. The primary outcome is mortality at day 90. Secondary outcomes are serious adverse events, serious adverse reactions, days alive at day 90 without life support, days alive and out of hospital at day 90, and mortality, health-related quality of life, and cognitive function at 1 year. We will conduct the statistical analyses according to a pre-defined statistical analysis plan, including three interim analyses. For the primary analysis we will use logistic regression adjusted for the stratification variables comparing the two interventions in the intention-to-treat population. Discussion The CLASSIC trial results will provide important evidence to guide clinicians' choice regarding IV fluid therapy in adults with septic shock.

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Background In patients with septic shock, mortality is high, and survivors experience long‐term physical, mental and social impairments. The ongoing Conservative vs Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial assesses the benefits and harms of a restrictive vs standard‐care intravenous (IV) fluid therapy. The hypothesis is that IV fluid restriction improves patient‐important long‐term outcomes. Aim To assess the predefined patient‐important long‐term outcomes in patients randomised into the CLASSIC trial. Methods In this pre‐planned follow‐up study of the CLASSIC trial, we will assess all‐cause mortality, health‐related quality of life (HRQoL) and cognitive function 1 year after randomisation in the two intervention groups. The 1‐year mortality will be collected from electronic patient records or central national registries in most participating countries. We will contact survivors and assess EuroQol 5‐Dimension, ‐5‐Level (EQ‐5D‐5L) and EuroQol‐Visual Analogue Scale and Montreal Cognitive Assessment 5‐minute protocol score. We will analyse mortality by logistic regression and use general linear models to assess HRQoL and cognitive function. Discussion With this pre‐planned follow‐up study of the CLASSIC trial, we will provide patient‐important data on long‐term survival, HRQoL and cognitive function of restrictive vs standard‐care IV fluid therapy in patients with septic shock.