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Clinical Research and Public HealthIn-Press PreviewClinical ResearchInfectious diseaseInflammation Open Access | 10.1172/JCI202480

Plasma chondroitin sulfate predicts the effectiveness of fluid resuscitation strategies in patients with sepsis

Kaori Oshima,1 Bailu Yan,2 Ran Tao,2 Gustavo Amorim,2 Chiara Di Gravio,3 Sarah A. McMurtry,4 Ryan C. Burke,5 Yunbi Nam,2 Ina Nikolli,1 Max S. Kravitz,5 Daniel Stephenson,6 Aaron Issaian,6 Kirk C. Hansen,6 Angelo D'Alessandro,6 Ivor S. Douglas,4 Wesley H. Self,7 Christopher J. Lindsell,8 Carolyn Leroux,9 Angelika Ringor,9 Michael A. Matthay,9 Jonathan S. Schildcrout,2 Nathan I. Shapiro,5 and Eric P. Schmidt1

1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

Find articles by Oshima, K. in: PubMed | Google Scholar

1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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1Department of Medicine, Mass General Brigham, Boston, United States of America

2Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States of America

3Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United States of America

4Department of Medicine, University of Colorado, Aurora, United States of America

5Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States of America

6Department of Biochemistry and Molecular Genetics, University of Colorado, Aurora, United States of America

7Vanderbilt Institute for Clinical and Translational Research and Department, Vanderbilt University Medical Center, Nashville, United States of America

8Department of Biostatistics and Bioinformatics and the Duke Clinical Resear, Duke University Medical Center, Durham, United States of America

9Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

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Published February 3, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI202480.
Copyright © 2026, Oshima et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 3, 2026 - Version history
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Abstract

BACKGROUND. Plasma heparan sulfate, a glycosaminoglycan released during endothelial glycocalyx degradation, predicts sepsis mortality. Chondroitin sulfate is a circulating glycosaminoglycan not specific to glycocalyx degradation; its relevance to sepsis is unknown.

METHODS. We studied the associations of plasma chondroitin sulfate with (a) mortality in patients with sepsis-associated hypotension and (b) the relative effectiveness of a randomly-assigned liberal versus restrictive intravenous fluid resuscitation strategy. We selected 574 patients enrolled in the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis trial using an outcome-enriched sampling strategy. We used liquid chromatography-mass spectrometry to quantify plasma chondroitin sulfate. In comparison, we measured hyaluronic acid as a glycocalyx degradation marker and IL-6 as an inflammatory biomarker. We conducted Cox proportional hazards regression analyses to examine associations of baseline biomarker concentrations with mortality and resuscitation strategy effectiveness. We used inverse probability of selection weights and generalized raking to account for the non-representative sampling design.

RESULTS. Plasma chondroitin sulfate, hyaluronic acid, and IL-6 were associated with mortality within 90 days. As baseline chondroitin sulfate increased, subsequent randomization to a restrictive strategy was increasingly beneficial (p = 0.022): treatment effect hazard ratio (restrictive versus liberal) for mortality was estimated as 1.49 (95% CI 0.98–2.27), 1.30 (1.00–1.69), 1.09 (0.82–1.44), 0.88 (0.66–1.16), and 0.71 (0.52–0.97) for 10th, 25th, 50th, 75th and 90th percentiles of baseline chondroitin sulfate.

CONCLUSIONS. Plasma chondroitin sulfate predicts sepsis mortality and may modify the response to a subsequent liberal vs. restrictive intravenous fluid resuscitation strategy.

TRIAL. ClinicalTrials.gov NCT03434028.

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