Elevated plasma levels of heparin-binding protein in intensive care unit patients with severe sepsis and septic shock

Abstract

Introduction: Rapid detection of, and optimized treatment for, severe sepsis and septic shock is crucial for successful outcome. Heparin-binding protein (HBP), a potent inducer of increased vascular permeability, is a potentially useful biomarker for predicting outcome in patients with severe infections. Our aim was to study the systemic release and dynamics of HBP in the plasma of patients with severe sepsis and septic shock in the ICU.

Methods: A prospective study was conducted of two patient cohorts treated in the ICU at Karolinska University Hospital Huddinge in Sweden. A total of 179 patients was included, of whom 151 had sepsis (126 with septic shock and 25 patients with severe sepsis) and 28 a non-septic critical condition. Blood samples were collected at five time points during six days after admission.

Results: HBP levels were significantly higher in the sepsis group as compared to the control group. At admission to the ICU, a plasma HBP concentration of ≥ 15 ng/mL and/or a HBP (ng/mL)/white blood cell count (109/L) ratio of >2 was found in 87.2% and 50.0% of critically ill patients with sepsis and non-septic illness, respectively. A lactate level of >2.5 mmol/L was detected in 64.9% and 56.0% of the same patient groups. Both in the sepsis group (n = 151) and in the whole group (n = 179), plasma HBP concentrations at admission and in the last measured sample within the 144 hour study period were significantly higher among 28-day non-survivors as compared to survivors and in the sepsis group, an elevated HBP-level at baseline was associated with an increased case-fatality rate at 28 days.

Conclusions: Plasma HBP levels were significantly higher in patients with severe sepsis or septic shock compared to patients with a non-septic illness in the ICU. HBP was associated with severity of disease and an elevated HBP at admission was associated with an increased risk of death. HBP that rises over time may identify patients with a deteriorating prognosis. Thus, repeated HBP measurement in the ICU may help monitor treatment and predict outcome in patients with severe infections.

Figure 1

Plasma levels of HBP and lactate, SOFA score at enrollment in the ICU, correlation with HBP and blood culture results, and HBP concentration and HBP/WBC ratio. Each dot represents the concentration in an individual plasma sample at enrollment of HBP (A) and lactate (B). C shows SOFA scores at enrollment. D describes HBP concentration in patients in comparison with blood culture results. E-F shows patients divided into non-leukopenic, leukopenic and controls describing HBP concentration (E), and HBP/WBC ratio (F). The patient groups are described in the Methods section. Bars represent median values. The suggested cut-off value for HBP is marked at 15 ng/mL (A, D-E) and ratio value 2 (F). Mann-Whitney´s non-parametric test was used for comparisons between the groups and P-values are given. Star symbols indicate significant difference (P <.05). Open circles represent patients with transient leukopenia, open triangles represent patients with persistent leukopenia, and open squares control patients with a positive blood culture. CRP, C-reactive protein; HBP, heparin-binding protein; SOFA, Sepsis-related Organ Failure Assessment; WBC, white blood cells.

Figure 2

HBP and lactate concentration over time and 28 day survival. Results from consecutive samplings for HBP (A) and lactate (B) over the study period. Plasma concentration for HBP (C-D) and lactate (E-F) in survivors and non-survivors after 28 days. SOFA score at enrollment in survivors and non-survivors (G-H). Mann-Whitney´s non-parametric test was used for comparisons between the groups and P -values are given. Star symbols indicate a significant difference (P <.05). The suggested cut-off value for HBP is marked at 15 ng/mL. Median values are given. HBP, heparin-binding protein; SOFA, Sepsis-related Organ Failure Assessment.

Figure 3

Kaplan-Meier survival estimates of 28-days mortality according to HBP-level >15 ng/mL or <15 ng/mL at inclusion. HBP, heparin-binding protein.