Higher baseline chondroitin sulfate predicts greater mortality benefit from restrictive fluid strategy in sepsisBlood marker may help predict which sepsis patients benefit from less fluid

The Journal of clinical investigation Published April 2, 2026 Study authors: Oshima Kaori, Yan Bailu, Tao Ran, Amorim Gustavo, Di Gravio Chiara, McMurtry Sarah A, Burke Ryan C, … PubMed ↗ NCT03434028 ↗ DOI ↗ Editorial oversight: Dr. Lars van Dijk, PhD · Surgical, Procedural & Diagnostic

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Key Takeaway

Consider plasma chondroitin sulfate as a potential predictive biomarker for fluid strategy response in sepsis, pending validation.

This study was a biomarker analysis nested within the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) randomized controlled trial. The analysis included 574 patients with sepsis-associated hypotension. The intervention compared was a restrictive intravenous fluid resuscitation strategy versus a liberal strategy, with the primary outcome being 90-day mortality.

The main finding was that baseline plasma chondroitin sulfate level modified the treatment effect. The hazard ratio for 90-day mortality (restrictive vs. liberal strategy) varied significantly by baseline chondroitin sulfate percentile (interaction P = 0.022). At the 10th percentile, the HR was 1.49 (95% CI 0.98-2.27), suggesting potential harm from restriction. At the 90th percentile, the HR was 0.71 (95% CI 0.52-0.97), suggesting benefit. As baseline chondroitin sulfate increased, randomization to the restrictive strategy was associated with a progressively lower hazard of death. Plasma hyaluronic acid and IL-6 were also associated with mortality.

Safety and tolerability data for the fluid strategies were not reported in this biomarker analysis. A key limitation is the use of an outcome-enriched sampling strategy, which required statistical weighting for analysis and may affect generalizability. The study was funded by NIH grants.

For practice, this analysis identifies plasma chondroitin sulfate as a potential modifier of response to fluid resuscitation strategy in sepsis, with higher levels predicting greater benefit from a restrictive approach. However, this represents a predictive association from a secondary analysis, not proven causality. Clinical implementation of this biomarker to guide fluid therapy would require prospective validation in independent cohorts.

Researchers looked at a blood marker called chondroitin sulfate in 574 patients with sepsis, a serious infection that causes low blood pressure. These patients were part of a trial comparing two fluid resuscitation strategies: a restrictive approach (giving less intravenous fluid) and a liberal approach (giving more fluid). The main goal was to see if this marker was linked to survival after 90 days.

They found that patients' response to the fluid strategy depended on their baseline chondroitin sulfate level. For patients with higher levels of this marker, the restrictive fluid strategy appeared more beneficial for survival. For those with lower levels, the benefit was less clear. The study did not report specific safety concerns or side effects for either approach.

It's important to be careful with these results. This was an analysis looking at associations within a larger trial, not a test of a new treatment. The researchers used a specialized sampling method that required statistical adjustments. The finding suggests chondroitin sulfate might help predict who responds better to which fluid strategy, but it does not prove the marker causes the difference or that it should be used in hospitals yet.

Readers should understand this is early research identifying a potential predictor. More studies are needed to confirm if measuring this marker can reliably help doctors choose the best fluid approach for individual sepsis patients.

What this means for you:

A blood marker may predict sepsis fluid response, but more research is needed before clinical use.

Study Details

Study typeRct

Sample sizen = 574

EvidenceLevel 2

PublishedApr 2026

PMID41632536

TrialNCT03434028

View Original Abstract ↓

BACKGROUNDPlasma 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.METHODSWe 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 nonrepresentative sampling design.RESULTSPlasma 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 (95% CI, 1.00-1.69), 1.09 (95% CI, 0.82-1.44), 0.88 (95% CI, 0.66-1.16), and 0.71 (95% CI, 0.52-0.97) for 10th, 25th, 50th, 75th, and 90th percentiles of baseline chondroitin sulfate.CONCLUSIONPlasma chondroitin sulfate predicts sepsis mortality and may modify the response to a subsequent liberal versus restrictive intravenous fluid resuscitation strategy.TRIAL REGISTRATIONClinicalTrials.gov NCT03434028.FUNDINGNIH grants R01HL149422 and R01HL094786.

Higher baseline chondroitin sulfate predicts greater mortality benefit from restrictive fluid strategy in sepsisBlood marker may help predict which sepsis patients benefit from less fluid

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Higher baseline chondroitin sulfate predicts greater mortality benefit from restrictive fluid strategy in sepsisBlood marker may help predict which sepsis patients benefit from less fluid

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