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Randomized Controlled Trial
. 2025 Aug 1;53(8):e1590-e1600.
doi: 10.1097/CCM.0000000000006679. Epub 2025 Apr 24.

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

Praleene Sivapalan  1   2 , Benjamin S Kaas-Hansen  1   2   3 , Tine S Meyhoff  1   2   4 , Peter B Hjortrup  2   5 , Maj-Brit N Kjær  1   2 , Jon H Laake  2   6 , Maria Cronhjort  2   7 , Stephan M Jakob  2   8 , Maurizio Cecconi  9   10 , Marek Nalos  2   11 , Marlies Ostermann  2   12 , Manu L N G Malbrain  2   13 , Morten H Møller  1   2   14 , Anders Perner  1   2   14 , Anders Granholm  1   2
Affiliations
Randomized Controlled Trial

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

Praleene Sivapalan et al. Crit Care Med. .

Abstract

Objectives: In the Conservative vs. Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) trial, restriction of IV fluid volumes led to similar overall mortality in ICU patients with septic shock. We assessed if variation in standard IV fluid treatment intensity across sites impacted the effects of fluid restriction.

Design: Secondary analysis of randomized clinical trial.

Setting: ICU.

Patients: The CLASSIC trial enrolled adult ICU patients with septic shock. We included 1366 participants from 19 sites, representing 88% of the full trial population. All sites with greater than or equal to 15 participants in the standard-fluid group were included in this study.

Interventions: Restrictive vs. standard IV fluid therapy.

Measurements and main results: We used machine learning (eXtreme Gradient Boosting) to predict the IV fluid volumes in the first 24 hours in the standard-fluid group while accounting for participant characteristics that could contribute to treatment variations. We then classified sites into intensity subgroups based on the mean differences between predicted and administered IV fluid volumes in the first 24 hours in the standard-fluid group. We assessed the intervention effects on mortality, serious adverse events and reactions, days alive without life support, and days alive out of hospital at day 90 across these intensity subgroups, using hierarchical Bayesian models with weakly informative priors. Sensitivity analyses evaluated intervention effects separately in each site. In the standard-fluid group, the median absolute difference between administered and predicted IV fluid volumes was -118 mL (interquartile range, -1,341 to 1,731 mL; full range, -5,873 to 11,761 mL). Sites were categorized into five intensity subgroups. The absolute differences in mortality across these subgroups ranged from -2.7% point to 1.4% point. We found similar effects of restrictive vs. standard IV fluid treatment on all outcomes within the intensity subgroups. Results were similar in the sensitivity analyses.

Conclusions: Among adult ICU patients with septic shock, variation in standard IV fluid volumes across sites did not substantially impact the effects of fluid restriction on outcomes after accounting for patient characteristics.

Trial registration: ClinicalTrials.gov NCT03668236.

Keywords: fluid therapy; heterogeneity in fluid treatment intensity; intensive care; machine learning; septic shock.

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References

    1. Evans L, Rhodes A, Alhazzani W, et al.: Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Med 2021; 47:1181–1247
    1. Sivapalan P, Ellekjaer KL, Jessen MK, et al.: Lower vs higher fluid volumes in adult patients with sepsis. Chest 2023; 164:892–912
    1. Meyhoff TS, Hjortrup PB, Wetterslev J, et al.; CLASSIC Trial Group: Restriction of intravenous fluid in ICU patients with septic shock. N Engl J Med 2022; 386:2459–2470
    1. Shapiro NI, Douglas IS BR, et al.; The National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network: Early restrictive or liberal fluid management for sepsis-induced hypotension. N Engl J Med 2023; 388:499–510
    1. Meyhoff TS, Hjortrup PB, Møller MH, et al.: Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial—protocol and statistical analysis plan. Acta Anaesthesiol Scand 2019; 63:1262–1271

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