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

David Andaluz-Ojeda, H Bryant Nguyen, Nicolas Meunier-Beillard, Ramón Cicuéndez, Jean-Pierre Quenot, Dolores Calvo, Auguste Dargent, Esther Zarca, Cristina Andrés, Leonor Nogales, Jose María Eiros, Eduardo Tamayo, Francisco Gandía, Jesús F Bermejo-Martín, Pierre Emmanuel Charles, David Andaluz-Ojeda, H Bryant Nguyen, Nicolas Meunier-Beillard, Ramón Cicuéndez, Jean-Pierre Quenot, Dolores Calvo, Auguste Dargent, Esther Zarca, Cristina Andrés, Leonor Nogales, Jose María Eiros, Eduardo Tamayo, Francisco Gandía, Jesús F Bermejo-Martín, Pierre Emmanuel Charles

Abstract

Background: The 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.

Methods: This 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.

Results: A 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).

Conclusions: The 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.

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

Figures

Fig. 1
Fig. 1
Kaplan–Meier analysis for mortality prediction at 28 days
Fig. 2
Fig. 2
AUROC analysis for identifying non-survivors at 28 days (entire cohort)
Fig. 3
Fig. 3
AUROC analysis for identifying non-survivors at 28 days depending on biomarker levels in the three severity groups

References

    1. Vincent J-L. Clinical sepsis and septic shock—definition, diagnosis and management principles. Langenbecks Arch Surg Dtsch Ges Für Chir. 2008;393:817–824. doi: 10.1007/s00423-008-0343-1.
    1. Jean-Baptiste E. Cellular mechanisms in sepsis. J Intensive Care Med. 2007;22:63–72. doi: 10.1177/0885066606297123.
    1. Hoyert DL, Xu J. Deaths: preliminary data for 2011. Natl Vital Stat Rep Cent Dis Control Prev Natl Cent Health Stat Natl Vital Stat Syst. 2012;61:1–51.
    1. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. On behalf of the working group on sepsis-related problems of the European society of intensive care medicine. Intensive Care Med. 1996;22:707–710. doi: 10.1007/BF01709751.
    1. Vincent J-L, Opal SM, Marshall JC. Ten reasons why we should NOT use severity scores as entry criteria for clinical trials or in our treatment decisions. Crit Care Med. 2010;38:283–287. doi: 10.1097/CCM.0b013e3181b785a2.
    1. Pierrakos C, Vincent J-L. Sepsis biomarkers: a review. Crit Care Lond Engl. 2010;14:R15. doi: 10.1186/cc8872.
    1. Hirata Y, Mitaka C, Sato K, Nagura T, Tsunoda Y, Amaha K, et al. Increased circulating adrenomedullin, a novel vasodilatory peptide, in sepsis. J Clin Endocrinol Metab. 1996;81:1449–1453.
    1. Müller-Redetzky HC, Will D, Hellwig K, Kummer W, Tschernig T, Pfeil U, et al. Mechanical ventilation drives pneumococcal pneumonia into lung injury and sepsis in mice: protection by adrenomedullin. Crit Care Lond Engl. 2014;18:R73. doi: 10.1186/cc13830.
    1. Pugin J. Adrenomedullin: a vasodilator to treat sepsis? Crit Care Lond Engl. 2014;18:152. doi: 10.1186/cc13924.
    1. Struck J, Tao C, Morgenthaler NG, Bergmann A. Identification of an adrenomedullin precursor fragment in plasma of sepsis patients. Peptides. 2004;25:1369–1372. doi: 10.1016/j.peptides.2004.06.019.
    1. Huang DT, Angus DC, Kellum JA, Pugh NA, Weissfeld LA, Struck J, et al. Midregional proadrenomedullin as a prognostic tool in community-acquired pneumonia. Chest. 2009;136:823–831. doi: 10.1378/chest.08-1981.
    1. Albrich WC, Dusemund F, Rüegger K, Christ-Crain M, Zimmerli W, Bregenzer T, et al. Enhancement of CURB65 score with proadrenomedullin (CURB65-A) for outcome prediction in lower respiratory tract infections: derivation of a clinical algorithm. BMC Infect Dis. 2011;11:112. doi: 10.1186/1471-2334-11-112.
    1. Krüger S, Ewig S, Giersdorf S, Hartmann O, Suttorp N, Welte T, et al. Cardiovascular and inflammatory biomarkers to predict short- and long-term survival in community-acquired pneumonia: results from the German Competence Network, CAPNETZ. Am J Respir Crit Care Med. 2010;182:1426–1434. doi: 10.1164/rccm.201003-0415OC.
    1. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM consensus conference committee. American College of Chest Physicians/Society of Critical Care Medicine. 1992. Chest. 2009;136:e28. doi: 10.1378/chest.09-2267.
    1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3) JAMA. 2016;315:801–810. doi: 10.1001/jama.2016.0287.
    1. Christ-Crain M, Morgenthaler NG, Struck J, Harbarth S, Bergmann A, Müller B. Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Crit Care Lond Engl. 2005;9:R816–R824. doi: 10.1186/cc3885.
    1. Suberviola B, Castellanos-Ortega A, Ruiz Ruiz A, Lopez-Hoyos M, Santibañez M. Hospital mortality prognostication in sepsis using the new biomarkers suPAR and proADM in a single determination on ICU admission. Intensive Care Med. 2013;39:1945–1952. doi: 10.1007/s00134-013-3056-z.
    1. Marino R, Struck J, Maisel AS, Magrini L, Bergmann A, Di Somma S. Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis. Crit Care Lond Engl. 2014;18:R34. doi: 10.1186/cc13731.
    1. Christ-Crain M, Morgenthaler NG, Stolz D, Müller C, Bingisser R, Harbarth S, et al. Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia [ISRCTN04176397] Crit Care Lond Engl. 2006;10:R96. doi: 10.1186/cc4955.
    1. Courtais C, Kuster N, Dupuy A-M, Folschveiller M, Jreige R, Bargnoux A-S, et al. Proadrenomedullin, a useful tool for risk stratification in high Pneumonia Severity Index score community acquired pneumonia. Am J Emerg Med. 2013;31:215–221. doi: 10.1016/j.ajem.2012.07.017.
    1. Renaud B, Schuetz P, Claessens Y-E, Labarère J, Albrich W, Mueller B. Proadrenomedullin improves risk of early admission to ICU score for predicting early severe community-acquired pneumonia. Chest. 2012;142:1447–1454. doi: 10.1378/chest.11-2574.
    1. Guignant C, Voirin N, Venet F, Poitevin F, Malcus C, Bohé J, et al. Assessment of pro-vasopressin and pro-adrenomedullin as predictors of 28-day mortality in septic shock patients. Intensive Care Med. 2009;35:1859–1867. doi: 10.1007/s00134-009-1610-5.
    1. Travaglino F, De Berardinis B, Magrini L, Bongiovanni C, Candelli M, Silveri NG, et al. Utility of procalcitonin (PCT) and mid regional pro-adrenomedullin (MR-proADM) in risk stratification of critically ill febrile patients in Emergency Department (ED). A comparison with APACHE II score. BMC Infect Dis. 2012;12:184. doi: 10.1186/1471-2334-12-184.
    1. Bello S, Lasierra AB, Mincholé E, Fandos S, Ruiz MA, Vera E, et al. Prognostic power of proadrenomedullin in community-acquired pneumonia is independent of aetiology. Eur Respir J. 2012;39:1144–1155. doi: 10.1183/09031936.00080411.
    1. Andaluz-Ojeda D, Cicuéndez R, Calvo D, Largo E, Nogales L, Muñoz MF, et al. Sustained value of proadrenomedullin as mortality predictor in severe sepsis. J Infect. 2015;71:136–139. doi: 10.1016/j.jinf.2015.02.002.

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