Diagnostic and prognostic value of procalcitonin and mid-regional pro-adrenomedullin in septic paediatric patients

Abstract

Early diagnosis of sepsis and its severity stratification at admission is critical to improve patient outcomes and to ensure the optimal use of health care resources. In order to assess the diagnostic potential of mid-regional pro-adrenomedullin (MR-proADM) in septic paediatric patients in comparison with procalcitonin (PCT), and to evaluate the usefulness of a single early determination of MR-proADM as a stratification and severity prediction tool, a prospective observational study was conducted. Seventy-three paediatric patients with a suspicion of sepsis were included. A single blood test was carried out at initial time to analyse infection biomarkers. PCT values were significantly higher in septic patients in comparison with non-septic patients (p = 0.03) with an AUC of 0.748 (p = 0.003). Levels of MR-proADM significantly increased in patients with severe sepsis (p = 0.048), with an AUC of 0.729 (p = 0.013). MR-proADM showed a positive correlation with pSOFA, PRISM III, and PELOD-2 severity scores. Levels of MR-proADM were significantly higher in patients who required vasoactive drugs (p = 0.02) or presented renal dysfunction (p = 0.004).

Conclusion: PCT appeared to be superior to MR-proADM in diagnosing sepsis. Determining MR-proADM plasma levels at the initial phase of sepsis could be a useful tool for sepsis stratification and morbidity prediction before organ failure occurs. The present results need to be assessed with larger sample size studies.

What is Known:
CRP and PCT are already included in clinical practice to assess sepsis and estimate disease severity, although their sensitivity and specificity are lower than desired.
•ADM is a protein that has immune and vascular modulation actions, and its blood levels are increased in adult and paediatric sepsis.
•ADM is a promising tool for early diagnosis and prognostic assessment in adult sepsis.
What is New:
PCT appeared to be superior to MR-proADM in diagnosing paediatric sepsis.
•MR-proADM plasma levels could be a useful tool for paediatric sepsis stratification and morbidity prediction.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

Abbreviations

ACCM:

American College of Critical Care Medicine

APACHE II:

Acute Physiology and Chronic Health disease Classification System II

AUC:

Area under the curve

CRP:

C-reactive protein.

GNB:

Gram-negative bacilli

GNC:

Gram-negative cocci

GNCB:

Gram-negative cocci-bacilli

GPC:

Gram-positive cocci

ICU:

Intensive care unit

IQR:

Interquartile ranges

L:

Litre

LH+:

Likelihood ratio

LOS:

Length of hospitalization

ml:

Millilitre

MR-proADM:

Mid-regional pro-adrenomedullin

MV:

Mechanical ventilation

ng:

Nanogram

nmol:

Nanomol

NPV:

Negative predictive value

PCT:

Procalcitonin

PELOD-2:

Paediatric Logistic Organ Dysfunction Score-2

PICU:

Paediatric Intensive Care Unit

PPV:

Positive predictive value

PRISM III:

Paediatric Risk of Mortality Score III

pSOFA:

paediatric Sequential Organ Failure Assessment

ROC:

Receiver operating characteristic

SAPS II:

Simplified Acute Physiology Score

Se:

Sensitivity

SOFA:

Sequential Organ Failure Assessment

SP:

Specificity

TRACE:

Time-Resolved Amplified Cryptate Emission

References

  1. 1.

    Weiss SL, Fitzgerald JC, Pappachan J, Wheeler D, Jaramillo-Bustamante JC, Salloo A, Singhi SC, Erickson S, Roy JA, Bush JL, Nadkarni VM, Thomas NJ, Sepsis Prevalence, Outcomes, and Therapies (SPROUT) Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network (2015) Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. Am J Respir Crit Care Med 191(10):1147–1157

    Article  Google Scholar 

  2. 2.

    Boeddha NP, Schlapbach LJ, Driessen GJ, Herberg JA, Rivero-Calle I, Cebey-López M, Klobassa DS, Philipsen R, de Groot R, Inwald DP, Nadel S, Paulus S, Pinnock E, Secka F, Anderson ST, Agbeko RS, Berger C, Fink CG, Carrol ED, Zenz W, Levin M, van der Flier M, Martinón-Torres F, Hazelzet JA, Emonts M, EUCLIDS consortium (2018) Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS). Crit Care 22(1):143

    Article  Google Scholar 

  3. 3.

    Sargentini V, Collepardo D, D Alessandro M, Petralito G, Ceccarelli G, Alessandri F et al (2017) Piciocchi A5, Angeloni A6, Venditti M3 BA. Role of biomarkers in adult sepsis and their application for a good laboratory practice: a pilot study. J Biol Regul Homeost Agents 31(4):1147–1154

    CAS  PubMed  Google Scholar 

  4. 4.

    Christ-Crain M, Morgenthaler NG, Struck J, Harbarth S, Bergmann A, Müller B (2005) Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Crit Care 9(6):R816–R824

    Article  Google Scholar 

  5. 5.

    Hirata Y, Mitaka C, Sato K, Nagura T, Tsunoda Y, Amaha K, Marumo F (1996) Increased circulating adrenomedullin, a novel vasodilatory peptide, in sepsis. J Clin Endocrinol Metab 81(4):1449–1453

    CAS  PubMed  Google Scholar 

  6. 6.

    Zudaire E, Portal-Núñez S, Cuttitta F (2006) The central role of adrenomedullin in host defense. J Leukoc Biol 80:237–244

    CAS  Article  Google Scholar 

  7. 7.

    Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T (1993) Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 192(2):553–560

    CAS  Article  Google Scholar 

  8. 8.

    Struck J, Tao C, Morgenthaler NG, Bergmann A (2004) Identification of an adrenomedullin precursor fragment in plasma of sepsis patients. Peptides. 25(8):1369–1372

    CAS  Article  Google Scholar 

  9. 9.

    Benito J, Luaces-Cubells C, Mintegi S, Astobiza E, Martinez-Indart L, Valls-Lafont A, García-García JJ (2013) Lack of value of midregional pro-adrenomedullin and C-terminal pro-endothelin-1 for prediction of severe bacterial infections in infants with fever without a source. Eur J Pediatr 172(11):1441–1449

    CAS  Article  Google Scholar 

  10. 10.

    Oncel MY, Dilmen U, Erdeve O, Ozdemir R, Calisici E, Yurttutan S, Canpolat FE, Oguz SS, Uras N (2012) Proadrenomedullin as a prognostic marker in neonatal sepsis. Pediatr Res 72(5):507–512

    CAS  Article  Google Scholar 

  11. 11.

    Angeletti S, Battistoni F, Fioravanti M, Bernardini S, Dicuonzo G (2013) Procalcitonin and mid-regional pro-adrenomedullin test combination in sepsis diagnosis. Clin Chem Lab Med 51(5):1059–1067

    CAS  Article  Google Scholar 

  12. 12.

    Suberviola B, Castellanos-Ortega A, Ruiz Ruiz A, Lopez-Hoyos M, Santibañez M (2013) Hospital mortality prognostication in sepsis using the new biomarkers suPAR and proADM in a single determination on ICU admission. Intensive Care Med 39(11):1945–1952

    CAS  Article  Google Scholar 

  13. 13.

    Matics TJ, Sanchez-Pinto LN (2017) Adaptation and validation of a pediatric sequential organ failure assessment score and evaluation of the Sepsis-3 definitions in critically ill children. JAMA Pediatr 171(10):e172352

    Article  Google Scholar 

  14. 14.

    Lacroix J, Cotting J (2005) Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Severity of illness and organ dysfunction scoring in children. Pediatr Crit Care Med 6(3):s126–s134

    Article  Google Scholar 

  15. 15.

    Jordan I, Corniero P, Balaguer M, Ortiz J, Vila D, Velasco J, Cambra FJ, Esteban E (2014) Adrenomedullin is a useful biomarker for the prognosis of critically ill septic children. Biomark Med 8(9):1065–1072

    CAS  Article  Google Scholar 

  16. 16.

    Rey C, García-Hernández I, Concha A, Martínez-Camblor P, Botrán M, Medina A, Prieto B, López-Herce J (2013) Pro-adrenomedullin, pro-endothelin-1, procalcitonin, C-reactive protein and mortality risk in critically ill children: a prospective study. Crit Care 17(5):R240

    Article  Google Scholar 

  17. 17.

    Davis AL, Carcillo JA, Aneja RK, Deymann AJ, Lin JC, Nguyen TC, Okhuysen-Cawley RS, Relvas MS, Rozenfeld RA, Skippen PW, Stojadinovic BJ, Williams EA, Yeh TS, Balamuth F, Brierley J, de Caen AR, Cheifetz IM, Choong K, Conway E Jr, Cornell T, Doctor A, Dugas MA, Feldman JD, Fitzgerald JC, Flori HR, Fortenberry JD, Graciano AL, Greenwald BM, Hall MW, Han YY, Hernan LJ, Irazuzta JE, Iselin E, van der Jagt E, Jeffries HE, Kache S, Katyal C, Kissoon N, Kon AA, Kutko MC, MacLaren G, Maul T, Mehta R, Odetola F, Parbuoni K, Paul R, Peters MJ, Ranjit S, Reuter-Rice KE, Schnitzler EJ, Scott HF, Torres A Jr, Weingarten-Arams J, Weiss SL, Zimmerman JJ, Zuckerberg AL (2017) American College of Critical Care Medicine clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock. Crit Care Med 45(6):1061–1093

    Article  Google Scholar 

  18. 18.

    Goldstein B, Giroir B, Randolph A (2005) International consensus conference on pediatric sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 6(1):2–8

    Article  Google Scholar 

  19. 19.

    Angeletti S, Spoto S, Fogolari M, Cortigiani M, Fioravanti M, De Florio L et al (2015) Diagnostic and prognostic role of procalcitonin (PCT) and MR-pro-Adrenomedullin (MR-proADM) in bacterial infections. APMIS. 123(9):740–748

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

All authors made substantial contributions to the study:Anna Solé-Ribalta contributed on conceptualization and design, methodology, investigation, data curation and formal analysis; Sara Bobillo-Pérez contributed on investigation, data curation and formal analysisAnna Valls contributed on methodology; Monica Girona-Alarcón contributed on conceptualization and design and investigation; Cristian Launes contributed on methodology and supervision; Francisco José Cambra contributed on investigation and supervision;Iolanda Jordán contributed on conceptualization and design, methodology, formal analysis and supervision;Elisabeth Esteban contributed on investigation formal analysis and supervision.

All authors also participated in the writing and/or revision of the manuscript: Anna Solé-Ribalta, Sara Bobillo-Pérez, Anna Valls, Monica Girona-Alarcon participated in drafting the initial manuscript; Anna Solé-Ribalta, Cristian Launes, Francisco José Cambra, Iolanda Jordan and Elisabeth Esteban participated in review and editing the manuscript.

All authors gave the final approval of the version to be published and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Iolanda Jordan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Communicated by Nicole Ritz

Electronic supplementary material

ESM 1

(DOCX 13 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Solé-Ribalta, A., Bobillo-Pérez, S., Valls, A. et al. Diagnostic and prognostic value of procalcitonin and mid-regional pro-adrenomedullin in septic paediatric patients. Eur J Pediatr 179, 1089–1096 (2020). https://doi.org/10.1007/s00431-020-03587-7

Download citation

Keywords

  • Sepsis
  • Adrenomedullin
  • Procalcitonin
  • Paediatric
  • Diagnosis
  • Stratification