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
View: Text | PDF
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

×

Figure 2

Plasma biomarkers as predictors of 90-day mortality in CLOVERS.

Options: View larger image (or click on image) Download as PowerPoint
Plasma biomarkers as predictors of 90-day mortality in CLOVERS. (A) Plas...
(A) Plasma chondroitin sulfate, (D) hyaluronic acid, and (G) IL-6 (measured only at 72 hours) were elevated at all time points in patients who died within 90 days of CLOVERS enrollment. The number of observations at each time point and P values from the Wald test of inverse probability weighted linear regression are shown under the violin plots. (B) Kaplan-Meier plot of the unadjusted association between baseline plasma chondroitin sulfate, divided into tertiles, and survival. Tertile ranges are listed in the legend, with the table beneath the plot indicating the number of observed participants at risk at each time. Kaplan-Meier estimates and the log rank test were calculated using inverse probability of selection weights. (C) Covariate-adjusted association of baseline (log-transformed) chondroitin sulfate with mortality rates within 90 days of randomization. To address concerns about violations of the proportional hazards assumption, this Cox model and all other Cox models are stratified by sex assigned at birth and chronic heart failure. Additionally, we estimated associations between SOFA score and log-hazard of death separately for 0–4 days, 5–11 days, and 12–90 days of follow-up. Due to the stratified sampling study design, we used generalized raking when fitting the model. Identical analyses were conducted to estimate the association between baseline plasma hyaluronic acid (E and F), IL-6 (H and I), and mortality rates within 90 days of randomization. Full covariate-adjusted models are demonstrated in Supplemental Figures 1–3.