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Published in: Annals of Intensive Care 1/2017

Open Access 01-12-2017 | Research

Adrenomedullin: a marker of impaired hemodynamics, organ dysfunction, and poor prognosis in cardiogenic shock

Authors: Heli Tolppanen, Mercedes Rivas-Lasarte, Johan Lassus, Jordi Sans-Roselló, Oliver Hartmann, Matias Lindholm, Mattia Arrigo, Tuukka Tarvasmäki, Lars Köber, Holger Thiele, Kari Pulkki, Jindrich Spinar, John Parissis, Marek Banaszewski, Jose Silva-Cardoso, Valentina Carubelli, Alessandro Sionis, Veli-Pekka Harjola, Alexandre Mebazaa

Published in: Annals of Intensive Care | Issue 1/2017

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Abstract

Background

The clinical CardShock risk score, including baseline lactate levels, was recently shown to facilitate risk stratification in patients with cardiogenic shock (CS). As based on baseline parameters, however, it may not reflect the change in mortality risk in response to initial therapies. Adrenomedullin is a prognostic biomarker in several cardiovascular diseases and was recently shown to associate with hemodynamic instability in patients with septic shock. The aim of our study was to evaluate the prognostic value and association with hemodynamic parameters of bioactive adrenomedullin (bio-ADM) in patients with CS.

Methods

CardShock was a prospective, observational, European multinational cohort study of CS. In this sub-analysis, serial plasma bio-ADM and arterial blood lactate measurements were collected from 178 patients during the first 10 days after detection of CS.

Results

Both bio-ADM and lactate were higher in 90-day non-survivors compared to survivors at all time points (P < 0.05 for all). Lactate showed good prognostic value during the initial 24 h (AUC 0.78 at admission and 0.76 at 24 h). Subsequently, lactate returned normal (≤2 mmol/L) in most patients regardless of later outcome with lower prognostic value. By contrast, bio-ADM showed increasing prognostic value from 48 h and beyond (AUC 0.71 at 48 h and 0.80 at 5–10 days). Serial measurements of either bio-ADM or lactate were independent of and provided added value to CardShock risk score (P < 0.001 for both). Ninety-day mortality was more than double higher in patients with high levels of bio-ADM (>55.7 pg/mL) at 48 h compared to those with low bio-ADM levels (49.1 vs. 22.6%, P = 0.001). High levels of bio-ADM were associated with impaired cardiac index, mean arterial pressure, central venous pressure, and systolic pulmonary artery pressure during the study period. Furthermore, high levels of bio-ADM at 48 to 96 h were related to persistently impaired cardiac and end-organ function.

Conclusions

Bio-ADM is a valuable prognosticator and marker of impaired hemodynamics in CS patients. High levels of bio-ADM may show shock refractoriness and developing end-organ dysfunction and thus help to guide therapeutic approach in patients with CS.
Study identifier of CardShock study NCT01374867 at clinicaltrials.gov
Appendix
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Literature
1.
go back to reference Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012;367(14):1287–96.CrossRefPubMed Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012;367(14):1287–96.CrossRefPubMed
2.
go back to reference Harjola VP, Lassus J, Sionis A, Kober L, Tarvasmaki T, Spinar J, et al. Clinical picture and risk prediction of short-term mortality in cardiogenic shock. Eur J Heart Fail. 2015;17(5):501–9 Epub 2015/03/31.CrossRefPubMed Harjola VP, Lassus J, Sionis A, Kober L, Tarvasmaki T, Spinar J, et al. Clinical picture and risk prediction of short-term mortality in cardiogenic shock. Eur J Heart Fail. 2015;17(5):501–9 Epub 2015/03/31.CrossRefPubMed
3.
go back to reference Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation. 2008;117(5):686–97.CrossRefPubMed Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation. 2008;117(5):686–97.CrossRefPubMed
4.
go back to reference Bakker J, Gris P, Coffernils M, Kahn RJ, Vincent JL. Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg. 1996;171(2):221–6.CrossRefPubMed Bakker J, Gris P, Coffernils M, Kahn RJ, Vincent JL. Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg. 1996;171(2):221–6.CrossRefPubMed
5.
go back to reference Attana P, Lazzeri C, Chiostri M, Picariello C, Gensini GF, Valente S. Lactate clearance in cardiogenic shock following ST elevation myocardial infarction: a pilot study. Acute Card Care. 2012;14(1):20–6.CrossRefPubMed Attana P, Lazzeri C, Chiostri M, Picariello C, Gensini GF, Valente S. Lactate clearance in cardiogenic shock following ST elevation myocardial infarction: a pilot study. Acute Card Care. 2012;14(1):20–6.CrossRefPubMed
6.
go back to reference Zhang Z, Xu X. Lactate clearance is a useful biomarker for the prediction of all-cause mortality in critically ill patients: a systematic review and meta-analysis*. Crit Care Med. 2014;42(9):2118–25.CrossRefPubMed Zhang Z, Xu X. Lactate clearance is a useful biomarker for the prediction of all-cause mortality in critically ill patients: a systematic review and meta-analysis*. Crit Care Med. 2014;42(9):2118–25.CrossRefPubMed
7.
go back to reference Katayama T, Nakashima H, Takagi C, Honda Y, Suzuki S, Yano K. Predictors of mortality in patients with acute myocardial infarction and cardiogenic shock. Circ J. 2005;69(1):83–8.CrossRefPubMed Katayama T, Nakashima H, Takagi C, Honda Y, Suzuki S, Yano K. Predictors of mortality in patients with acute myocardial infarction and cardiogenic shock. Circ J. 2005;69(1):83–8.CrossRefPubMed
8.
go back to reference 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. 2014;18(1):R34.CrossRefPubMedPubMedCentral 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. 2014;18(1):R34.CrossRefPubMedPubMedCentral
9.
go back to reference Pio R, Martinez A, Unsworth EJ, Kowalak JA, Bengoechea JA, Zipfel PF, et al. Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners. J Biol Chem. 2001;276(15):12292–300.CrossRefPubMed Pio R, Martinez A, Unsworth EJ, Kowalak JA, Bengoechea JA, Zipfel PF, et al. Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners. J Biol Chem. 2001;276(15):12292–300.CrossRefPubMed
10.
go back to reference Lewis LK, Smith MW, Yandle TG, Richards AM, Nicholls MG. Adrenomedullin(1-52) measured in human plasma by radioimmunoassay: plasma concentration, adsorption, and storage. Clin Chem. 1998;44(3):571–7.PubMed Lewis LK, Smith MW, Yandle TG, Richards AM, Nicholls MG. Adrenomedullin(1-52) measured in human plasma by radioimmunoassay: plasma concentration, adsorption, and storage. Clin Chem. 1998;44(3):571–7.PubMed
11.
go back to reference Struck J, Tao C, Morgenthaler NG, Bergmann A. Identification of an Adrenomedullin precursor fragment in plasma of sepsis patients. Peptides. 2004;25(8):1369–72.CrossRefPubMed Struck J, Tao C, Morgenthaler NG, Bergmann A. Identification of an Adrenomedullin precursor fragment in plasma of sepsis patients. Peptides. 2004;25(8):1369–72.CrossRefPubMed
12.
go back to reference Di Somma S, Magrini L, Travaglino F, Lalle I, Fiotti N, Cervellin G, et al. Opinion paper on innovative approach of biomarkers for infectious diseases and sepsis management in the emergency department. Clin Chem Lab Med. 2013;51(6):1167–75.CrossRefPubMed Di Somma S, Magrini L, Travaglino F, Lalle I, Fiotti N, Cervellin G, et al. Opinion paper on innovative approach of biomarkers for infectious diseases and sepsis management in the emergency department. Clin Chem Lab Med. 2013;51(6):1167–75.CrossRefPubMed
13.
go back to reference Harrell FE. Regression modeling strategies with applications to linear models, logistic regression, and survival analysis. New York: Springer; 2001. Harrell FE. Regression modeling strategies with applications to linear models, logistic regression, and survival analysis. New York: Springer; 2001.
14.
go back to reference Hartmann O, Schuetz P, Albrich WC, Anker SD, Mueller B, Schmidt T. Time-dependent Cox regression: serial measurement of the cardiovascular biomarker proadrenomedullin improves survival prediction in patients with lower respiratory tract infection. Int J Cardiol. 2012;161(3):166–73.CrossRefPubMed Hartmann O, Schuetz P, Albrich WC, Anker SD, Mueller B, Schmidt T. Time-dependent Cox regression: serial measurement of the cardiovascular biomarker proadrenomedullin improves survival prediction in patients with lower respiratory tract infection. Int J Cardiol. 2012;161(3):166–73.CrossRefPubMed
15.
go back to reference Tzikas S, Keller T, Ojeda FM, Zeller T, Wild PS, Lubos E, et al. MR-proANP and MR-proADM for risk stratification of patients with acute chest pain. Heart. 2013;99(6):388–95.CrossRefPubMed Tzikas S, Keller T, Ojeda FM, Zeller T, Wild PS, Lubos E, et al. MR-proANP and MR-proADM for risk stratification of patients with acute chest pain. Heart. 2013;99(6):388–95.CrossRefPubMed
16.
go back to reference Potocki M, Breidthardt T, Reichlin T, Morgenthaler NG, Bergmann A, Noveanu M, et al. Midregional pro-adrenomedullin in addition to b-type natriuretic peptides in the risk stratification of patients with acute dyspnea: an observational study. Crit Care. 2009;13(4):R122.CrossRefPubMedPubMedCentral Potocki M, Breidthardt T, Reichlin T, Morgenthaler NG, Bergmann A, Noveanu M, et al. Midregional pro-adrenomedullin in addition to b-type natriuretic peptides in the risk stratification of patients with acute dyspnea: an observational study. Crit Care. 2009;13(4):R122.CrossRefPubMedPubMedCentral
17.
go back to reference Shah RV, Truong QA, Gaggin HK, Pfannkuche J, Hartmann O, Januzzi JL Jr. Mid-regional pro-atrial natriuretic peptide and pro-adrenomedullin testing for the diagnostic and prognostic evaluation of patients with acute dyspnoea. Eur Heart J. 2012;33(17):2197–205.CrossRefPubMedPubMedCentral Shah RV, Truong QA, Gaggin HK, Pfannkuche J, Hartmann O, Januzzi JL Jr. Mid-regional pro-atrial natriuretic peptide and pro-adrenomedullin testing for the diagnostic and prognostic evaluation of patients with acute dyspnoea. Eur Heart J. 2012;33(17):2197–205.CrossRefPubMedPubMedCentral
18.
go back to reference Maisel A, Mueller C, Nowak RM, Peacock WF, Ponikowski P, Mockel M, et al. Midregion prohormone adrenomedullin and prognosis in patients presenting with acute dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial. J Am Coll Cardiol. 2011;58(10):1057–67.CrossRefPubMed Maisel A, Mueller C, Nowak RM, Peacock WF, Ponikowski P, Mockel M, et al. Midregion prohormone adrenomedullin and prognosis in patients presenting with acute dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial. J Am Coll Cardiol. 2011;58(10):1057–67.CrossRefPubMed
19.
go back to reference Lassus J, Gayat E, Mueller C, Peacock WF, Spinar J, Harjola VP, et al. Incremental value of biomarkers to clinical variables for mortality prediction in acutely decompensated heart failure: the Multinational Observational Cohort on Acute Heart Failure (MOCA) study. Int J Cardiol. 2013;168(3):2186–94 Epub 2013/03/30.CrossRefPubMed Lassus J, Gayat E, Mueller C, Peacock WF, Spinar J, Harjola VP, et al. Incremental value of biomarkers to clinical variables for mortality prediction in acutely decompensated heart failure: the Multinational Observational Cohort on Acute Heart Failure (MOCA) study. Int J Cardiol. 2013;168(3):2186–94 Epub 2013/03/30.CrossRefPubMed
20.
go back to reference Katayama T, Nakashima H, Honda Y, Suzuki S, Yano K. Relationship between adrenomedullin and left-ventricular systolic function and mortality in acute myocardial infarction. Angiology. 2005;56(1):35–42.CrossRefPubMed Katayama T, Nakashima H, Honda Y, Suzuki S, Yano K. Relationship between adrenomedullin and left-ventricular systolic function and mortality in acute myocardial infarction. Angiology. 2005;56(1):35–42.CrossRefPubMed
21.
go back to reference Khan SQ, O’Brien RJ, Struck J, Quinn P, Morgenthaler N, Squire I, et al. Prognostic value of midregional pro-adrenomedullin in patients with acute myocardial infarction: the LAMP (Leicester Acute Myocardial Infarction Peptide) study. J Am Coll Cardiol. 2007;49(14):1525–32.CrossRefPubMed Khan SQ, O’Brien RJ, Struck J, Quinn P, Morgenthaler N, Squire I, et al. Prognostic value of midregional pro-adrenomedullin in patients with acute myocardial infarction: the LAMP (Leicester Acute Myocardial Infarction Peptide) study. J Am Coll Cardiol. 2007;49(14):1525–32.CrossRefPubMed
22.
go back to reference Luyt CE, Landivier A, Leprince P, Bernard M, Pavie A, Chastre J, et al. Usefulness of cardiac biomarkers to predict cardiac recovery in patients on extracorporeal membrane oxygenation support for refractory cardiogenic shock. J Crit Care. 2012;27(5):524e7-14.CrossRef Luyt CE, Landivier A, Leprince P, Bernard M, Pavie A, Chastre J, et al. Usefulness of cardiac biomarkers to predict cardiac recovery in patients on extracorporeal membrane oxygenation support for refractory cardiogenic shock. J Crit Care. 2012;27(5):524e7-14.CrossRef
23.
go back to reference Onitsuka H, Imamura T, Yamaga J, Kuwasako K, Kitamura K, Eto T. Angiotensin II stimulates cardiac adrenomedullin production and causes accumulation of mature adrenomedullin independently of hemodynamic stress in vivo. Horm Metab Res. 2005;37(5):281–5.CrossRefPubMed Onitsuka H, Imamura T, Yamaga J, Kuwasako K, Kitamura K, Eto T. Angiotensin II stimulates cardiac adrenomedullin production and causes accumulation of mature adrenomedullin independently of hemodynamic stress in vivo. Horm Metab Res. 2005;37(5):281–5.CrossRefPubMed
24.
go back to reference Sugo S, Minamino N, Shoji H, Kangawa K, Kitamura K, Eto T, et al. Interleukin-1, tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells. Biochem Biophys Res Commun. 1995;207(1):25–32.CrossRefPubMed Sugo S, Minamino N, Shoji H, Kangawa K, Kitamura K, Eto T, et al. Interleukin-1, tumor necrosis factor and lipopolysaccharide additively stimulate production of adrenomedullin in vascular smooth muscle cells. Biochem Biophys Res Commun. 1995;207(1):25–32.CrossRefPubMed
25.
go back to reference Kato J, Tsuruda T, Kita T, Kitamura K, Eto T. Adrenomedullin: a protective factor for blood vessels. Arterioscler Thromb Vasc Biol. 2005;25(12):2480–7.CrossRefPubMed Kato J, Tsuruda T, Kita T, Kitamura K, Eto T. Adrenomedullin: a protective factor for blood vessels. Arterioscler Thromb Vasc Biol. 2005;25(12):2480–7.CrossRefPubMed
26.
go back to reference von Haehling S, Filippatos GS, Papassotiriou J, Cicoira M, Jankowska EA, Doehner W, et al. Mid-regional pro-adrenomedullin as a novel predictor of mortality in patients with chronic heart failure. Eur J Heart Fail. 2010;12(5):484–91.CrossRef von Haehling S, Filippatos GS, Papassotiriou J, Cicoira M, Jankowska EA, Doehner W, et al. Mid-regional pro-adrenomedullin as a novel predictor of mortality in patients with chronic heart failure. Eur J Heart Fail. 2010;12(5):484–91.CrossRef
27.
go back to reference Nishio K, Akai Y, Murao Y, Doi N, Ueda S, Tabuse H, et al. Increased plasma concentrations of adrenomedullin correlate with relaxation of vascular tone in patients with septic shock. Crit Care Med. 1997;25(6):953–7.CrossRefPubMed Nishio K, Akai Y, Murao Y, Doi N, Ueda S, Tabuse H, et al. Increased plasma concentrations of adrenomedullin correlate with relaxation of vascular tone in patients with septic shock. Crit Care Med. 1997;25(6):953–7.CrossRefPubMed
28.
go back to reference Mebazaa A, Yilmaz MB, Levy P, Ponikowski P, Peacock WF, Laribi S, et al. Recommendations on pre-hospital & early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine. Eur J Heart Fail. 2015;17(6):544–58 Epub 2015/05/23.CrossRefPubMed Mebazaa A, Yilmaz MB, Levy P, Ponikowski P, Peacock WF, Laribi S, et al. Recommendations on pre-hospital & early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine. Eur J Heart Fail. 2015;17(6):544–58 Epub 2015/05/23.CrossRefPubMed
29.
go back to reference Thiele H, Ohman EM, Desch S, Eitel I, de Waha S. Management of cardiogenic shock. Eur Heart J. 2015;36(20):1223–30 Epub 2015/03/04.CrossRefPubMed Thiele H, Ohman EM, Desch S, Eitel I, de Waha S. Management of cardiogenic shock. Eur Heart J. 2015;36(20):1223–30 Epub 2015/03/04.CrossRefPubMed
30.
go back to reference Mebazaa A, Tolppanen H, Mueller C, Lassus J, DiSomma S, Baksyte G, et al. Acute heart failure and cardiogenic shock: a multidisciplinary practical guidance. Intensive Care Med. 2016;42(2):147–63.CrossRefPubMed Mebazaa A, Tolppanen H, Mueller C, Lassus J, DiSomma S, Baksyte G, et al. Acute heart failure and cardiogenic shock: a multidisciplinary practical guidance. Intensive Care Med. 2016;42(2):147–63.CrossRefPubMed
31.
go back to reference Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;18(8):891–975.CrossRef Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;18(8):891–975.CrossRef
32.
go back to reference Kohsaka S, Menon V, Lowe AM, Lange M, Dzavik V, Sleeper LA, et al. Systemic inflammatory response syndrome after acute myocardial infarction complicated by cardiogenic shock. Arch Intern Med. 2005;165(14):1643–50.CrossRefPubMed Kohsaka S, Menon V, Lowe AM, Lange M, Dzavik V, Sleeper LA, et al. Systemic inflammatory response syndrome after acute myocardial infarction complicated by cardiogenic shock. Arch Intern Med. 2005;165(14):1643–50.CrossRefPubMed
33.
go back to reference Task Force on the management of STseamiotESoC, Steg PG, James SK, Atar D, Badano LP, Blomstrom-Lundqvist C, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33(20):2569–619.CrossRef Task Force on the management of STseamiotESoC, Steg PG, James SK, Atar D, Badano LP, Blomstrom-Lundqvist C, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33(20):2569–619.CrossRef
34.
go back to reference O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al. ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e362–425.CrossRefPubMed O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, et al. ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e362–425.CrossRefPubMed
35.
go back to reference Rihal CS, Naidu SS, Givertz MM, Szeto WY, Burke JA, Kapur NK, et al. 2015 SCAI/ACC/HFSA/STS Clinical Expert Consensus Statement on the use of percutaneous mechanical circulatory support devices in cardiovascular care: endorsed by the American Heart Association, the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia Intervencion; Affirmation of Value by the Canadian Association of Interventional Cardiology-Association Canadienne de Cardiologie d’intervention. J Am Coll Cardiol. 2015;65(19):e7–26.CrossRefPubMed Rihal CS, Naidu SS, Givertz MM, Szeto WY, Burke JA, Kapur NK, et al. 2015 SCAI/ACC/HFSA/STS Clinical Expert Consensus Statement on the use of percutaneous mechanical circulatory support devices in cardiovascular care: endorsed by the American Heart Association, the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia Intervencion; Affirmation of Value by the Canadian Association of Interventional Cardiology-Association Canadienne de Cardiologie d’intervention. J Am Coll Cardiol. 2015;65(19):e7–26.CrossRefPubMed
36.
go back to reference Werdan K, Gielen S, Ebelt H, Hochman JS. Mechanical circulatory support in cardiogenic shock. Eur Heart J. 2014;35(3):156–67.CrossRefPubMed Werdan K, Gielen S, Ebelt H, Hochman JS. Mechanical circulatory support in cardiogenic shock. Eur Heart J. 2014;35(3):156–67.CrossRefPubMed
Metadata
Title
Adrenomedullin: a marker of impaired hemodynamics, organ dysfunction, and poor prognosis in cardiogenic shock
Authors
Heli Tolppanen
Mercedes Rivas-Lasarte
Johan Lassus
Jordi Sans-Roselló
Oliver Hartmann
Matias Lindholm
Mattia Arrigo
Tuukka Tarvasmäki
Lars Köber
Holger Thiele
Kari Pulkki
Jindrich Spinar
John Parissis
Marek Banaszewski
Jose Silva-Cardoso
Valentina Carubelli
Alessandro Sionis
Veli-Pekka Harjola
Alexandre Mebazaa
Publication date
01-12-2017
Publisher
Springer Paris
Published in
Annals of Intensive Care / Issue 1/2017
Electronic ISSN: 2110-5820
DOI
https://doi.org/10.1186/s13613-016-0229-2

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