Circulating precursor levels of endothelin-1 and adrenomedullin, two endothelium-derived, counteracting substances, in sepsis

Abstract

Plasma levels of endothelin-1 (ET-1) and adrenomedullin (ADM), two opposingly acting peptides, correlate with mortality in endotoxemia, but their measurement is cumbersome. New sandwich assays have been introduced that measure more stable precursor fragments. The objective of this study was to investigate the counterplay of their precursor peptides in septic patients and to compare them with disease severity and other biomarkers. Blood samples of an observational study in 95 consecutive critically ill patients admitted to the intensive care unit (ICU) were analyzed. CT-proET-1 and MR-proADM concentrations on admission were measured using new sandwich immunoassays. Depending on the clinical severity of the infection, both CT-proET-1 and MR-proADM levels exhibited a gradual increase from Systemic Inflammatory Response Syndrome (SIRS) to sepsis and septic shock (p < .001). Compared to the group of survivors, the group of nonsurvivors had higher median values of MR-proADM (5.7 nmol/L [range 0.4 to 21.0] versus 1.9 nmol/L [range 0.3 to 17.1], p < .02) and similar CT-proET-1 levels (56.0pmol/L [range 0.5 to 271.0] versus 54.1pmol/L [range 1.0 to 506.0], p = .86). Receiver operating characteristics (ROC) curve analysis showed a higher prognostic accuracy of the calculated ratio of both counteracting substances as compared to CT-proET-1 (p = 0.001) and C-reactive protein (CRP) (p = .001) and in the range of MR-proADM (p = .51), procalcitonin (p = 0.22), and the APACHE II score (p = .61). Endothelin-1 and adrenomedullin precursor peptides gradually increase with increasing severities of infection in critically ill patients. The ratio of the two counteracting peptides correlates with mortality and shows a prognostic accuracy to predict adverse outcome comparable to the APACHE II score.

Figures

FIG. 1.

CT-proET-1 and MR-proADM values in all patients according to the severity of disease. Patients' data on admission to the ICU were grouped according to the severity of the disease following consensus criteria in groups with “SIRS, but no sepsis,” “sepsis,” and “septic shock.” Squares denote median values and whiskers indicate 25th and 75th percentiles.

FIG. 2.

CT-proET-1-, MR-proADM, and the calculated ratio in surviving as compared to nonsurviving patients. Data from all patients on admission are shown. Squares denote median values, boxes represent 25th to 75th percentiles and whiskers indicate the range.

FIG. 3.

Receiver operating curve (ROC) analysis of CT-proET1, MRproADM, the CT-proET1/MR-proADM ratio and the APACHE II score with respect to outcome prediction of critically ill patients. Receiver operating characteristic (ROC) plots are graphical plots illustrating the sensitivity (y-axis) and the specificity (x -axis) for all cut-off points of a diagnostic or prognostic test. The overall performance and a summary measure of the diagnostic accuracy of a test can be expressed as the area under the ROC curve (AUC). Note that an AUCof 0.50 means that the diagnostic accuracy in question is equivalent to that which would be obtained by flipping a coin (i.e., random chance). (a) Data of all patients (n = 95) with SIRS and sepsis on admission to the ICU. Sensitivity was calculated with nonsurvivors (n = 21), specificity with survivors (n = 74) during their hospital stay. (b) Data of patients with sepsis (including septic shock) in need for blood pressure support with vasoactiva (n = 30) on admission to the ICU. Sensitivity was calculated with nonsurvivors (n = 9), specificity with survivors (n = 21) during their hospital stay.