The use of mid-regional proadrenomedullin to identify disease severity and treatment response to sepsis - a secondary analysis of a large randomised controlled trial

Abstract

Background: This study assessed the ability of mid-regional proadrenomedullin (MR-proADM) in comparison to conventional biomarkers (procalcitonin (PCT), lactate, C-reactive protein) and clinical scores to identify disease severity in patients with sepsis.

Methods: This is a secondary analysis of a randomised controlled trial in patients with severe sepsis or septic shock across 33 German intensive care units. The association between biomarkers and clinical scores with mortality was assessed by Cox regression analysis, area under the receiver operating characteristic and Kaplan-Meier curves. Patients were stratified into three severity groups (low, intermediate, high) for all biomarkers and scores based on cutoffs with either a 90% sensitivity or specificity.

Results: 1089 patients with a 28-day mortality rate of 26.9% were analysed. According to the Sepsis-3 definition, 41.2% and 58.8% fulfilled the criteria for sepsis and septic shock, with respective mortality rates of 20.0% and 32.1%. MR-proADM had the strongest association with mortality across all Sepsis-1 and Sepsis-3 subgroups and could facilitate a more accurate classification of low (e.g. MR-proADM vs. SOFA: N = 265 vs. 232; 9.8% vs. 13.8% mortality) and high (e.g. MR-proADM vs. SOFA: N = 161 vs. 155; 55.9% vs. 41.3% mortality) disease severity. Patients with decreasing PCT concentrations of either ≥ 20% (baseline to day 1) or ≥ 50% (baseline to day 4) but continuously high MR-proADM concentrations had a significantly increased mortality risk (HR (95% CI): 19.1 (8.0-45.9) and 43.1 (10.1-184.0)).

Conclusions: MR-proADM identifies disease severity and treatment response more accurately than established biomarkers and scores, adding additional information to facilitate rapid clinical decision-making and improve personalised sepsis treatment.

Keywords: Biomarkers; MR-proADM; Mortality; SOFA; Sepsis; Septic shock.

Fig. 1

Prediction of 28-day mortality at baseline. Association between biomarkers and clinical scores with mortality at baseline, with respective AUROC and Cox regression analyses across the total patient population (a), Sepsis-3 (b) and Septic shock-3 (c) subgroups. All multivariate analyses for 28-day mortality were significant (p < 0.001). APACHE II Acute Physiological and Chronic Health Evaluation II score, AUROC area under the receiver operating characteristic curve, CI confidence interval, CRP C-reactive protein, HR hazard ratio, IQR interquartile range, MR-proADM mid-regional proadrenomedullin, N number, PCT procalcitonin, SAPS II, Simplified Acute Physiological Score II, SOFA Sequential Organ Failure Assessment

Fig. 2

Cox regression and AUROC analysis for 28-day mortality prediction based on SOFA severity levels. Biomarker and clinical score performance in predicting 28-day mortality with respective AUROC and Cox regression analyses in the low (SOFA ≤7) (a), moderate (SOFA 8–13) (b) and high (SOFA ≥14) (c) severity SOFA subgroups. APACHE II Acute Physiological and Chronic Health Evaluation II score, AUROC area under the receiver operating characteristic curve, CI confidence interval, CRP C-reactive protein, HR hazard ratio, IQR interquartile range, MR-proADM mid-regional proadrenomedullin, N number, PCT procalcitonin, SAPS II Simplified Acute Physiological Score II, SOFA Sequential Organ Failure Assessment

Fig. 3

Mortality rates at 28 and 90 days following PCT and MR-proADM kinetics between baseline and day 1. Kaplan-Meier plots illustrate patient subgroups stratified by MR-proADM severity levels for 90-day mortality, based on corresponding PCT concentrations from baseline to day 1, decreasing either by ≥ 20% (a) or by < 20% (b). Severity levels are grouped as continuously low, intermediate or high, or as a composite for increasing or decreasing MR-proADM levels. Individual hazard ratios for comparisons between patient subgroups are indicated: *continuously intermediate vs. low values; **continuously high vs. intermediate values; ***continuously high vs. low values; †increasing low to intermediate vs. continuously low values; ††increasing intermediate to high vs. continuously intermediate values; ‡decreasing high to intermediate vs. continuously high values; ‡‡decreasing intermediate to low vs. continuously intermediate values. HR hazard ratio, IQR interquartile range, MR-proADM mid-regional proadrenomedullin, N number, PCT procalcitonin