Plasma chondroitin sulfate predicts the effectiveness of fluid resuscitation strategies in patients with sepsis
Kaori Oshima, Bailu Yan, Ran Tao, Gustavo Amorim, Chiara Di Gravio, Sarah A. McMurtry, Ryan C. Burke, Yunbi Nam, Ina Nikolli, Max S. Kravitz, Daniel Stephenson, Aaron Issaian, Kirk C. Hansen, Angelo D’Alessandro, Ivor S. Douglas, Wesley H. Self, Christopher J. Lindsell, Carolyn Leroux, Angelika Ringor, Michael A. Matthay, Jonathan S. Schildcrout, Nathan I. Shapiro, Eric P. Schmidt
Kaori Oshima, Bailu Yan, Ran Tao, Gustavo Amorim, Chiara Di Gravio, Sarah A. McMurtry, Ryan C. Burke, Yunbi Nam, Ina Nikolli, Max S. Kravitz, Daniel Stephenson, Aaron Issaian, Kirk C. Hansen, Angelo D’Alessandro, Ivor S. Douglas, Wesley H. Self, Christopher J. Lindsell, Carolyn Leroux, Angelika Ringor, Michael A. Matthay, Jonathan S. Schildcrout, Nathan I. Shapiro, Eric P. Schmidt
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Clinical Research and Public Health Clinical Research Infectious disease Inflammation

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

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 nonrepresentative 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 (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.CONCLUSION Plasma chondroitin sulfate predicts sepsis mortality and may modify the response to a subsequent liberal versus restrictive intravenous fluid resuscitation strategy.TRIAL REGISTRATION ClinicalTrials.gov NCT03434028.FUNDING NIH grants R01HL149422 and R01HL094786.

Authors

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

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Figure 4

The effectiveness of the randomized treatment assignment is modified by (log of) baseline chondroitin sulfate but not hyaluronic acid or IL-6 plasma concentrations.

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The effectiveness of the randomized treatment assignment is modified by ...
Panels display results from models that added an interaction between randomized treatment assignment and baseline log-transformed plasma chondroitin sulfate (A and B), hyaluronic acid (C and D), or IL-6 (E and F) to the models shown in Figure 2, C, F, and I. Panels on the left demonstrate hazard ratios comparing restrictive versus liberal fluid resuscitation and pointwise 95% CIs across the distribution of log of baseline chondroitin sulfate (A), hyaluronic acid (C), or IL-6 (E) concentrations. The densities at the bottom of the panels refer to the distribution of baseline (log-transformed) plasma biomarker concentrations across the CLOVERS cohort, and for reference, we highlight the 10th, 25th, 50th, 75th, and 90th percentiles with dotted lines. We show the P values associated with (a) the overall treatment effect and (b) the heterogeneity of treatment effect. The heterogeneity of treatment effect test is a 2 degrees of freedom test Against the null hypothesis that the treatment effect is constant across the distribution of the biomarker values. The overall treatment effect test includes the main effect of the intervention (randomized fluid resuscitation strategy) and the 2 terms for the interaction with biomarker values. It is a test against the null hypothesis that treatment has no effect on mortality rates within 90 days of randomization against the alternative that it has any effect. Panels on the right demonstrate estimated hazard ratio and pointwise 95% CI comparing baseline log chondroitin sulfate (B), hyaluronic acid (D), or IL-6 (F) values to a reference value when the hazard ratio of the restrictive versus liberal fluid resuscitation strategies is equal to one. The associations are displayed separately for those randomized to the restrictive and liberal fluid resuscitation strategies.