Superior accuracy of mid-regional proadrenomedullin for mortality prediction in sepsis with varying levels of illness severity

Abstract

BackgroundThe use of novel sepsis biomarkers has increased in recent years. However, their prognostic value with respect to illness severity has not been explored. In this work, we examined the ability of mid-regional proadrenomedullin (MR-proADM) in predicting mortality in sepsis patients with different degrees of organ failure, compared to that of procalcitonin, C-reactive protein and lactate.MethodsThis was a two-centre prospective observational cohort, enrolling severe sepsis or septic shock patients admitted to the ICU. Plasma biomarkers were measured during the first 12 h of admission. The association between biomarkers and 28-day mortality was assessed by Cox regression analysis and Kaplan–Meier curves. Patients were divided into three groups as evaluated by the Sequential Organ Failure Assessment (SOFA) score. The accuracy of the biomarkers for mortality was determined by area under the receiver operating characteristic curve (AUROC) analysis.ResultsA total of 326 patients with severe sepsis (21.7%) or septic shock (79.3%) were enrolled with a 28-day mortality rate of 31.0%. Only MR-proADM and lactate were associated with mortality in the multivariate analysis: hazard ratio 8.5 versus 3.4 (p < 0.001). MR-proADM showed the best AUROC for mortality prediction at 28 days in the analysis over the entire cohort (AUROC [95% CI] 0.79 [0.74–0.84]) (p < 0.001). When patients were stratified by the degree of organ failure, MR-proADM was the only biomarker to predict mortality in all severity groups (SOFA ≤ 6, SOFA = 7–12, and SOFA ≥ 13), AUROC [95% CI] of 0.75 [0.61–0.88], 0.74 [0.66–0.83] and 0.73 [0.59–0.86], respectively (p < 0.05). All patients with MR-proADM concentrations ≤0.88 nmol/L survived up to 28 days. In patients with SOFA ≤ 6, the addition of MR-proADM to the SOFA score increased the ability of SOFA to identify non-survivors, AUROC [95% CI] 0.70 [0.58–0.82] and 0.77 [0.66–0.88], respectively (p < 0.05 for both).ConclusionsThe performance of prognostic biomarkers in sepsis is highly influenced by disease severity. MR-proADM accuracy to predict mortality is not affected by the degree of organ failure. Thus, it is a good candidate in the early identification of sepsis patients with moderate disease severity but at risk of mortality.Electronic supplementary materialThe online version of this article (doi:10.1186/s13613-017-0238-9) contains supplementary material, which is available to authorized users.

MR‐ proADM to detect specific types of organ failure in infection

“…Our results demonstrate that MR‐proADM was the biomarker independently associated with the largest number of organ failure types (five out of the six considered in the SOFA score). This probably explains why MR‐proADM was also the best biomarker predicting mortality, which is consistent with previous findings 28 . AUROC analysis evidenced that accuracy of MR‐proADM was the highest to detect cardiovascular and renal failure (with areas > 0.80 in both cases).…”

Correlation between Serum Mid-Regional Pro-Adrenomedullin and Sequential Organ Failure Assessment (SOFA) Score in Patient with Sepsis

“…The level of MR proADM in this study ranged from 0.74 to 36.6 nmol/L. This level tends to be higher compared to the results of the study conducted by Andaluz et al 4 . The difference in the level of MR proADM is caused by several possibilities.…”

“…The half-life of MR proADM is longer than that of ADM since its half-life is 2-3 hours whereas the halflife of ADM is only 22 minutes. 4 When infection occurs, the endothelial layer of blood vessel is damaged. The damage to the endothelium will activate the nucleus factor kappa β (NF-kB) to synthesize ADM from MR proADM.…”

Biomarkers and clinical scores to aid the identification of disease severity and intensive care requirement following activation of an in-hospital sepsis code

“…Elke et al [25] previously found differences in performance depending on whether the infecting agent consisted solely of Gram positive vs. negative bacteria, as well as highlighting the influence of prior surgical procedures in patients directly admitted onto the ICU. A further ICU study by Andaluz-Ojeda et al [2] in 326 patients with severe sepsis or septic shock, as well as that of Enguix-Armada [30] in 388 patients with septic shock, also found MR-proADM to have the highest predictive value compared to conventional biomarkers such as PCT, CRP and lactate, although interestingly, the greatest performance was found in patients with a lower degree of organ failure. Nevertheless, no subgroup analysis was performed in either study relating to location of infection development or prior surgical history.…”

“…A standardised set of defined criteria to aid in the early identification of sepsis therefore remains elusive, despite the established use of specific parameters in conditions such as myocardial infarction and pulmonary embolism [2]. Furthermore, the poor acceptance of previous [3] and current [4,5] definitions has led to significant debate concerning the most appropriate clinical criteria required to make an accurate diagnosis.…”